Workshop 2: Modelling of Tissue Growth and Form

(March 6,2017 - March 10,2017 )

Organizers


Mark Alber
Mathematics, University of California, Riverside
Dagmar Iber
D-BSSE, ETH Zurich
Paul Kulesa
Developmental Biology, Stowers Institute for Medical Research
Philip Maini
Mathematical Institute, University of Oxford

This workshop is specifically devoted to study problems in morphogenesis and development in which growth and mechanics play a key role.

By its very nature, biology raises many challenges that mathematical modellers have not had to address in other areas of application. For example, in early development there is an enormous amount of growth of tissue and large-scale tissue rearrangements. During these processes there are significant mechanical changes and, in many cases, the phenomena are intrinsically three-dimensional. Thus, even the crudest models pose computational challenges. Once proposed, models must be validated and here is another challenge. How does one image complex evolving surfaces and extract summary metrics for model validation?

There are a number of ways to model growth and rearrangement. The purely continuum approach describes tissue as a visco-elastic-plastic deformable material satisfying the laws of continuum mechanics. This approach has the advantages of generating a small system of (albeit highly nonlinear) coupled partial differential equations with a limited number of parameters and a history of mathematical theory underpinning them. The disadvantages are that they are too coarse to account for changes in cell shape or for cell-level properties. To account for the latter, discrete cell-based models have been developed (for example, cell-centred, vertex, Potts). These allow for extraction of detailed metrics on cell size, number of sides (in the case of epithelial tissues, which are well approximated by polygonal cell shapes) etc., which, in principle, can be compared with data. Disadvantages are that there are many more free parameters in such models, and there is no rigorous mathematical theory underlying these models. Whichever modelling framework is adopted, there is the challenge of model parameterization, identifiability and validation.

This workshop is timely because of the advances in computational techniques that now allow us to begin to compute the outcome of the above modelling approaches, and because of the rapidly developing field of imaging which is beginning to provide data for model validation. Therefore the lack of reliable and detailed spatiotemporal data, the major stumbling block for the acceptance of such models, may now become somewhat less of issue, putting us on the threshold of a new era of model validation and application.

The workshop will have two underlying themes:

  1. Specific applications. These will include, but are not limited to, tissue (for example, brain) mechanics, growth and shaping of sea shells, epithelial sheet dynamics (for example, growth control in Drosophila wing disc), neural crest cell invasion, etc;
  2. Mathematical challenges. These include, developing a theory to underpin many of the different modelling approaches so that they can be compared with each other; addressing the problems that arise in gathering summary metrics and subsequent model validation, new computational techniques for partial differential equations on evolving surfaces.

Accepted Speakers

Ruth Baker
Wolfson Centre for Mathematical Biology, Mathematical Institute, University of Oxford
James Briscoe
Developmental Dynamics, The Francis Crick Institute
Fernando Casares
Universidad Pablo de Olavide, Centro Andaluz de Biologia del Desarrollo
Cheng-Ming Chuong
Keck School of Medicine, Dept. of Pathology, USC
Alex Fletcher
School of Mathematics and Statistics, University of Sheffield
Alain Goriely
Mathematics, University of Oxford
Jeremy Green
Dept of Craniofacial Development & Stem Cell Biology, King's College London
Laura Johnston
Genetics and Development, Columbia University
Rusty Lansford
PIBBS, University of Southern California
Yanlan Mao
MRC LMCB, University College London
Miquel Marin-Riera
Centre of Excellence in Experimental and Computational Developmental Biology, University of Helsinki
Sean Megason
Systems Biology, Harvard Medical School
Celeste Nelson
Chemical & Biological Engineering, Princeton University
Qing Nie
Biomedical Engineering & Mathematics, University of California, Irvine
Andrew Oates
epfl, 'Ecole Polytechnique F'ed'erale de Lausanne (EPFL)
Hans Othmer
School of Mathematics, University of Minnesota
Richard Schneider
Orthopaedic Surgery, University of California at San Francisco
James Sharpe
Systems Biology, Centre for Genomic Regulation
Troy Shinbrot
Biomedical Engineering, Rutgers University
David Umulis
Ag. and Biological Engineering, Purdue University
Fengzhu Xiong
Genetics, Harvard Medical School
Jeremy Zartman
Chemical and Biomolecular Engineering, University of Notre Dame
Monday, March 6, 2017
Time Session
08:00 AM

Shuttle to MBI

08:15 AM
09:00 AM

Breakfast

09:00 AM
09:15 AM

Introduction by MBI Staff

09:15 AM
09:30 AM

Logistics of the Meeting/Organizers

09:30 AM
10:00 AM
James Briscoe - The growth and patterning of the vertebrate neural tube

The generation of the correct neuronal subtype at the appropriate position and time in the vertebrate neural tube is the first step in the assembly of functional neural circuits. It also represents one of the best-studied examples of embryonic pattern formation. Distinct neuronal subtypes are generated in a precise spatial order from progenitor cells according to their location along the anterior-posterior and dorsal-ventral axes. Underpinning this organization is a complex network of extrinsic and intrinsic factors. Particularly well understood is the mechanism that determines the generation of different neuronal subtypes in ventral regions of the spinal cord. In this region of the nervous system, the secreted protein Sonic Hedgehog (Shh) acts in graded fashion to organize the pattern of neurogenesis. This is a dynamic process in which increasing concentrations and durations of exposure to Shh generate neurons with successively more ventral identities. Interactions between the receiving cells and the graded signal underpin the mechanism of Shh action. In particular, the regulation of transcription factors induced or repressed by Shh signaling play an essential role in determining the graded response of cells. Thus the accurate patterning of the neural tube and the specification of motor neurons and the other neuronal subtypes characteristic of this region relies on the continuous processing and constant refinement of the cellular response to graded Shh signaling.

10:00 AM
10:10 AM

Discussion

10:10 AM
10:40 AM

Break

10:40 AM
11:10 AM
James Sharpe - The relationship between growth and form in the developing limb bud

The vertebrate limb bud is a classical model system for developmental biology – with the advantage of having been studied for many decades. Despite this, and despite its relatively simple shape, a consensus model of its physical morphogenesis has not been reached. I will introduce our own hypothesis on limb bud morphogenesis, and contrast it to previous ideas. I will introduce our 3D dynamical model which captures this hypothesis (a Cellular Potts Model) and also discuss a key theme of this workshop – how to get the right balance in course-graining a model: too many details or too few?

11:10 AM
11:20 AM

Discussion

11:20 AM
11:50 AM
Jeremy Green - Beyond apical constriction: vertical telescoping and other novel models of epithelial bending

Epithelial bending is a fundamental process of developmental morphogenesis from the earliest stages of gastrulation to the final stages of organogenesis. Classically, epithelia bend by apical constriction in which apical actin contraction forces cells to become wedge-shaped. Established alternatives are “basal wedging” of the median hinge of the neural tube (in which wedge-shaped cells are formed by basal localization of nuclei and “bsal relaxation” in chick otic vesicle invagination and Drosophila leg folds (in which wedging occurs by basal expansion due to actin disassembly). We investigated invagination of epithelia to form tooth buds, hair follicles, and mammary ducts. We discovered that here cell wedging is driven cell-extrinsically by contraction of overlying (suprabasal) tissue in a thickening placode. In this “canopy contraction” mechanism, contractile force created by intercalation of suprabasal cells is transmitted to the basal lamina by apical protrusions of flanking “shoulder cells”. We found that, surprisingly, salivary glands (which are genetically closely related to tooth buds, hair follicles, etc.) invaginate without a suprabasal canopy and without cell wedging. Instead, cells shear vertically in an entirely novel process we call “vertical telescoping”. This vertical shear is driven by cells coordinately climbing over their more central basal neighbours by means of centripetally directed apical protrusions. Protrusion-driven cell shear unifies vertical telescoping with canopy contraction while explaining the different morphologies observed among a diverse family of epithelial invaginations. Modelling of adhesive interactions is underway.

11:50 AM
12:00 PM

Discussion

12:00 PM
02:30 PM

Lunch Break

02:30 PM
03:00 PM
Richard Schneider - Developmental Mechanisms Underlying the Evolution of Form and Function in the Jaw

How does form arise during development and change during evolution? How does form relate to function, and in particular, what processes allow structures of embryos to presage their later use in adults? To address these questions, we perform experiments that leverage the distinct jaw anatomies of duck and quail. Much like that found in humans, duck develop a pronounced secondary cartilage at the tendon insertion of their jaw adductor muscle on the coronoid process of the mandible. An equivalent secondary cartilage is absent in quail and other species such as mice. We focus on the role of neural crest mesenchyme (NCM), which produces all the cartilages and bones in the jaw skeleton. NCM also makes muscle connective tissues including ligaments and tendons. In contrast, jaw muscles are derived from mesoderm. Transplanting NCM from quail to duck generates quail-like pattern in the jaw skeleton and accompanying musculature, which in turn causes a loss of secondary cartilage on the coronoid process. Moreover, paralyzing muscle or blocking Transforming Growth Factor-Beta (TGFb) and Fibroblast Growth Factor (FGF) signaling also inhibits secondary chondrogenesis on the coronoid process. Thus, we hypothesize that species-specific differences in TGFb and FGF signaling, jaw architecture, and mechanical forces promote formation of secondary cartilage on the coronoid process of duck versus quail. We test this hypothesis by evaluating the extent to which TGFb and FGF signaling are NCM-mediated, and we use loss-of-function approaches to determine precisely when and where these pathways induce secondary cartilage at the coronoid process. We also investigate the link between jaw architecture and mechanical forces at the mandibular adductor using 3D reconstructions and a finite element model. Additionally, we block mechanotransduction to understand how the local mechanical environment regulates molecular programs for secondary cartilage. By investigating the effects of NCM-mediated signaling, musculoskeletal anatomy, and mechanical forces on the induction of secondary cartilage, this work offers insights mechanisms that link form and function during development and evolution.

03:00 PM
03:10 PM

Discussion

03:10 PM
03:40 PM
Miquel Marin-Riera - Predicting principles of tissue growth and mechanics through the modelling of tooth morphogenesis

We want to understand the mechanisms that drive cell movement and tissue deformation during morphogenesis in order to predict how changes in development produce morphological variation that is relevant for evolution. We use the mammalian tooth as a model system due to the large variation it shows across the phylogenetic tree and its relatively well known development. Despite an extensive knowledge on the molecular pathways regulating the patterning and morphogenesis of the developing tooth, little is known about how individual cells move and what mechanisms are driving these movements. In order to shed light on those mechanisms, we design a mathematical model of tooth development in which cell movements are driven by compressive and tensile mechanical forces originating from tissue growth and cell-cell adhesion. The model is set to reproduce the transition between mouse molar bud (E13) and cap cap stages (E15), during which two epithelial folds protrude from the epithelial tooth germ and surround the underlying mesenchyme. When we fit the tissue specific growth rates in the model to the ones estimated from experimental data, the model correctly predicts the morphology of the tooth germ and the directionality of cell trajectories in the epithelial compartment. The model also predicts that different spatial patterns of mechanical forces arise when the adhesion strength between different cell types is varied. In order to validate the model predictions we experimentally infer the forces by means of mechanical perturbations on dissected tooth germs. We conclude that a simple model of differential growth and adhesion is able to explain the morphology, patterns of cell movement and partially the mechanical forces generated during tooth development. We argue that the addition of active cell migration might be required in order to improve the model predictions.

03:40 PM
03:50 PM

Discussion

03:50 PM
06:30 PM

Reception and Poster Session in MBI Lounge

06:30 PM

Shuttle pick-up from MBI

Tuesday, March 7, 2017
Time Session
08:00 AM

Shuttle to MBI

08:15 AM
09:00 AM

Breakfast

09:00 AM
09:30 AM
Fernando Casares - Eyes, large and small: variation of eye size in Drosophila and beyond.

Animals are characterized by their morphology €“to such an extent that most often we recognize different species for their unique shape and size. Since organs are the product of development, mechanisms must exist to ensure the constancy of organ size and shape within a given species. However, these mechanisms need also to be plastic, as organ morphology has varied €“and in some instances, very remarkably€“ during evolution. In the lab we investigate the mechanisms that regulate organ size by studying the eyes of flies. €œEyes€? because they are specialized sensory structures of great biological relevance; and specifically €œof flies€? because eyes have undergone an extraordinary morphological and functional diversification within this huge insect group €“the diptera. Typically, flies possess two eye types: small dorsal eyes (called €œocelli€?) and large, lateral eyes. Although the development of both eye types is controlled by the same morphogen, Hedgehog (Hh), I will discuss the different strategies used by these two eye types to control their small or large size. I will further present work, that combines experimentation and mathematical modeling, aimed at identifying the changes in biological processes that might be responsible for the variation of eye size during evolution, and the limits to that variation.

09:30 AM
09:40 AM

Discussion

09:40 AM
10:10 AM
Laura Johnston - Cell competition: a mechanism that promotes developmental stability

Development is a robust process that yields remarkably reproducible body size and bilaterally symmetric appendages. In Drosophila, developmental stability is tightly regulated and even small deviations from bilateral symmetry - known as fluctuating asymmetry (FA) - are quite rare. During growth, cells within organs behave as social communities and use comparisons of cell fitness to foster cooperation. Cells perceived as unfit are eliminated from the tissue via cell competition, which promotes precise organ size control and optimal organ fitness. Mutations in genes required for cell competition lead to loss of bilaterally symmetric wings, increasing wing FA. Dilp8 is a secreted peptide that via its neuronally expressed receptor, Lgr3, coordinates tissue growth with developmental timing by gating ecdysone production in the prothoracic gland. Loss of dilp8 or lgr3 leads to strong FA in adult wings, and also prevents cell competition. We will present results of experiments designed to reveal how Dilp8 and cell competition are functionally linked in a mechanism that promotes optimal animal fitness.

10:10 AM
10:20 AM

Discussion

10:20 AM
10:50 AM

Break

10:50 AM
11:20 AM
David Umulis - Mathematical modeling and image analysis of BMP-mediated patterning in developing zebrafish embryos

Bone Morphogenetic Proteins (BMPs) act in developmental pattern formation as a paradigm of extracellular information that is passed from an extracellular morphogen to cells that process the information and differentiate into distinct cell types based on the morphogen level. Numerous extracellular modulators and feedback regulators establish and control the BMP signaling distribution along the dorsal-ventral (DV) embryonic axis in vertebrates to induce space and time-dependent patterns of gene expression. To identify how the dynamic pattern is regulated during development, we have developed a seamless data-to-model integration and optimization strategy. First, the nuclear intensities of fluorescent stained Phosphorylated-Smad5 (P-Smad) are acquired for each nuclei in each embryo from staged populations to provide a quantitative time-course for the BMP signaling gradient. Next, the nuclei are segmented to yield quantitative point-clouds of P-Smad level at each nuclei. The individual point clouds are registered to similarly staged embryos using a process called Coherent Point Drift (CPD) and the registered populations provide rigorous quantification of BMP signaling. To delineate the mechanism of BMP signal inhibition by the secreted binding proteins Chordin (Chd), and Noggin (Nog) a mathematical model was developed and optimized against the population data for wild type and Chd mutants. The results of the data-driven computational model will be presented.

11:20 AM
11:30 AM

Discussion

11:30 AM
02:00 PM

Lunch Break

02:00 PM
03:40 PM

Open Time for Individual Interactions and Discussions on "What should be the next steps/challenges?"

03:40 PM
04:10 PM
Fengzhu Xiong - Mechanical coupling coordinates the co-elongation of axial and paraxial tissues

The embryonic body axis is composed of tissues that elongate at the same pace despite exhibiting strikingly different cellular organization. Whether their co-elongation is coordinated remains unclear. Here we report evidence of mechanical coupling between axial and paraxial tissues. Combining microsurgery and live-imaging in avian embryos, we found that the presomitic mesoderm (PSM) compresses the neural tube and notochord promoting their convergence and elongation. Computational simulation predicts cell motility in the PSM to generate compression that causes axial tissues to push the caudal progenitor domain, which we tested experimentally. Surprisingly, this axial push is in turn required for the progenitor addition that sustains PSM growth. Together our results show that forces produced by collective cell dynamics couple different elongating tissues into an engine-like positive feedback loop.

04:10 PM
04:20 PM

Discussion

04:20 PM
04:50 PM
Cheng-Ming Chuong - The feather as a platform for mathematical modeling

The geometric forms and exquisite arrangement patterns of the feather provide a great opportunity for mathematical modeling. The accessibility for manipulation and imaging of cell behaviors in the relatively flat embryonic chicken skin allow experimental verification and identification of molecular basis of the modeling parameters. In the adult bird, feathers regenerate with distinct form, pigmentation, and arrangement, leading to the spectacular plumage patterns (Chuong and Richardson edit, 2009, Pattern Formation, IJDB). We have been using this multi-scale platform to collaborate with experts in mathematical modeling and have gained a deeper understanding of morphogenesis. Here are some examples we have done or are developing. 1. Periodic patterning involving Turing principles (Jung et al., 1998 DB; Maini et al.,2006, Science). 2. How collective cell behavior in developing skin that translate molecular signals into tissue patterns (Lin et al., 2009 DB; Model by Baker). Recent 4D imaging reveals even more complex behavior (ongoing). 3. Feather exhibits distinct branching forms: radial symmetry, bilateral symmetry, and bilateral symmetry in development and evolution (Li et al., Nat Comm, 2017; Model by Qing Nie). 4. Feathers exhibit pigment patterns with a feather (micro-patterning, Lin et al., 2013; Science) and across the body (Macro-patterning, ongoing). 5. In a feather tract (population), an intra-dermal muscle network is assembled using existing follicle as the reference points, and the network configuration is adaptable in respond to external stimuli (Wu et al., in prep; Model by Baker).

04:50 PM
05:00 PM

Discussion

05:00 PM

Shuttle pick-up from MBI

Wednesday, March 8, 2017
Time Session
08:00 AM

Shuttle to MBI

08:15 AM
09:00 AM

Breakfast

09:00 AM
09:30 AM
Hans Othmer - Models of Cell Motility

We will discuss how mechanics and signaling can be incorporated in cell-based models and used in a variety of contexts, including tissue growth and cell movement.

09:30 AM
09:40 AM

Discussion

09:40 AM
10:10 AM
Yanlan Mao - Getting in Shape: in vivo and in silico studies of tissue mechanics in growth control

How tissue size and shape are controlled is a fundamental biological question that remains remarkably ill understood. Using a combination of genetics, live imaging, experimental biophysics and computational modeling, we show that tissue mechanical forces can have an instrumental role in controlling cell shape patterns and cell division orientations. We show that differential proliferation rates can generate global patterns of mechanical tension to orient tissue growth in a self perpetuating and self organizing manner. These patterns of mechanical forces can also drive cytoskeletal rearrangements and 3D tissue morphogenesis.

10:10 AM
10:20 AM

Discussion

10:20 AM
10:50 AM

Break

10:50 AM
11:20 AM
Rusty Lansford - Direct and dynamic lineage analysis in amniote embryos
11:20 AM
11:30 AM

Discussion

11:30 AM
02:00 PM

Lunch Break

02:00 PM
02:30 PM
Jeremy Zartman - Tissue-level communication through patterning of intercellular calcium wave dynamics

Identification of the cell-cell communication mechanisms that integrate information at multiple hierarchical scales from cells to the whole organism is a grand challenge for developmental biology with broad implications in regenerative medicine. In particular, how some organs can recover from wounding and repair tissue patterning is still largely a mystery. One critical component during wound healing and regeneration is the regulation of calcium (Ca2+) ions, which are second messengers that integrate information from multiple signaling pathways. Here we characterize periodic intercellular Ca2+ waves (ICWs) in a model organ system of epithelial growth and patterning€”the Drosophila wing imaginal disc. We developed a novel regulated environment for micro-organs (REM-Chip) device that enable a broad range of genetic, chemical and mechanical perturbations during live imaging and have created an image processing pipeline to analyze Ca2+ dynamics. We propose that the patterning of ICWs reflects underlying morphogenetic patterning of developing tissues and that the ICWs provide information transmission between compartments within the organ. Long distance communication networks through gap junctions thus could provide a general physiological-based mechanism for coordinating cellular activity in epithelial tissues during development and wound healing. Thus, integrative mechanistic insights into the cross-talk between Ca2+ and morphogen signaling pathways have a broad range of potential medical applications including for diagnostics and therapeutics. Long-term efforts are focused on developing integrative predictive models that connect Ca2+ signaling dynamics to cell and tissue mechanical properties.

02:30 PM
02:40 PM

Discussion

02:40 PM
03:10 PM
Troy Shinbrot - Cellular Morphogenesis in Silico

Recent advances in the in silico modeling of cellular dynamics now permit explicit analysis of cellular structure formation. This provides the scientific community with the capability of testing hypotheses in precisely controlled environments for the first time. We describe an agent-based approach that simulates cells that reproduce, migrate and change shape. We find that both expected morphologies and previously unreported patterns spontaneously self-assemble. Most of the states found computationally have been observed in vitro, and it remains to be established what role these self-assembled states may play in in vivo morphogenesis.

03:10 PM
03:20 PM

Discussion

03:20 PM
04:00 PM

Break

04:00 PM
05:00 PM
Alain Goriely - Special Seminar: On Growth and Form and Mathematics: D'Arcy Thompson, 100 years on

TBD

05:00 PM
05:30 PM

Discussion

05:30 PM
07:30 PM

Reception

07:30 PM

Shuttle pick-up from MBI

Thursday, March 9, 2017
Time Session
08:00 AM

Shuttle to MBI

08:15 AM
09:00 AM

Breakfast

09:00 AM
10:30 AM

Discussion: What do you take home from this workshop?

10:30 AM
11:00 AM

Break

11:00 AM
11:30 AM
Ruth Baker - Cell biology processes: model building and validation using quantitative data

Cell biology processes such as motility, proliferation and death are essential to a host of phenomena such as development, wound healing and tumour invasion, and a huge number of different modelling approaches have been applied to study them. In this talk I will explore a suite of related models for the growth and invasion of cell populations. These models take into account different levels of detail on the spatial locations of cells and, as a result, their predictions can differ depending on the relative magnitudes of the various model parameters. To this end, I will discuss how one might determine the applicability of each of these models, and the extent to which inference techniques can be used to estimate their parameters, using both cell- and population-level quantitative data.

11:30 AM
11:40 AM

Discussion

11:40 AM
02:00 PM

Lunch Break

02:00 PM
02:30 PM
Andrew Oates - Period and Pattern in the Embryo

The segmentation clock is a multi-cellular patterning system of genetic oscillators thought to control the rhythmic and sequential formation of the vertebrate embryo's body segments. Individual oscillating cells are synchronized with their neighbors, forming a coherent wave pattern of gene expression. How these wave patterns arise and how they are regulated during embryogenesis is not clear. I will describe recent progress in understanding the behavior of individual cells as they slow their oscillations and differentiate during segmentation, and discuss how this gives rise to the tissue-level wave patterns.

02:30 PM
02:40 PM

Discussion

02:40 PM
03:10 PM
Celeste Nelson - Mechanics of epithelial morphogenesis

Cell-generated mechanical forces drive many of the tissue movements and rearrangements that are required to transform simple populations of cells into the complex three-dimensional geometries of mature organs. However, mechanical forces do not need to arise from active cellular movements. Here, I will describe recent studies that have illuminated the roles of passive mechanical forces resulting from mechanical instabilities between epithelial tissues and their surroundings. These mechanical instabilities cause essentially one-dimensional epithelial tubes and two-dimensional epithelial sheets to buckle or wrinkle into complex topologies containing loops, folds, and undulations in organs as diverse as the brain, the intestine, and the lung. Our work suggests a new class of tissue development - buckling or wrinkling morphogenesis - and that this morphogenetic mechanism may be broadly responsible for sculpting organ form. Harnassing these mechanical instabilities represents an intriguing strategy for engineering organs ex vivo.

03:10 PM
03:20 PM

Discussion

03:20 PM
03:50 PM

Break

03:50 PM
04:20 PM
Qing Nie - Data-driven multiscale and stochastic modeling of cell fate dynamics in tissue growth

In tissue growth and morphogenesis, cells make fate decisions in response to different and dynamic environmental and pathological stimuli. Recently, there has been an explosion of experimental data at various biological scales, including gene expression and epigenetic measurements at the single cell level. While such data provide some details related to cellular states at a particular scale, many gaps remain in our knowledge and understanding of how cells make their dynamic and spatial decisions in tissue growth. Here we present multiscale and stochastic models in analyzing single-cell molecular data and their connections with spatial tissue dynamics. Our approach requires development of new mathematical and computational tools in machine learning, stochastic analysis and simulations, and PDEs with moving boundaries. We will use our data-driven multiscale approach to delineate several novel mechanisms or principles underlining spatial cell fate dynamics in development and regeneration.

04:20 PM
04:30 PM

Discussion

04:30 PM

Shuttle pick-up from MBI

06:30 PM
07:00 PM

Cash Bar

07:00 PM
09:00 PM

Banquet in the Fusion Room @ Crowne Plaza Hotel

Friday, March 10, 2017
Time Session
08:00 AM

Shuttle to MBI

08:15 AM
09:00 AM

Breakfast

09:00 AM
09:30 AM
Sean Megason - Size control of somites via a clock and scaled gradient

My lab combines in toto imaging in zebrafish embryos, with mathematical modeling, and molecular and mechanical perturbations to try to understand how groups of cells work together to form patterns and shapes. I will discuss three recent stories in my lab focussed on understanding how tissue/organ size is controlled. In the inner ear we find that size is primarily controlled by negative feedback between flux of fluid into the otic vessicle and hydrostatic pressure. For somites, we find that size is controlled by scaling of a molecular gradient. And in the neural tube we find that size is controlled based on mechanical feedback on differentiation rate.

09:30 AM
09:40 AM

Discussion

09:40 AM
10:10 AM

Break

10:10 AM
10:40 AM
Alex Fletcher - Cell-based modelling of epithelial morphogenesis

Embryonic epithelia achieve complex morphogenetic movements through the coordinated action and rearrangement of individual cells. In combination with experimental approaches, computational modelling can provide insight into these processes. In this talk I describe our application of vertex models, a widely-used class of computational model for epithelia, to investigate the role of patterned cell mechanics in two settings in the Drosophila embryo: tissue size control and convergent extension. I highlight the biological insights gained through this work and conclude by presenting some recent extensions to 3D morphogenesis.

10:40 AM
10:50 AM

Discussion

11:00 AM

Shuttle pick-up from MBI (One to airport and one back to hotel)

Name Email Affiliation
Adamer, Michael michael.adamer@merton.ox.ac.uk Mathematical Institute, University of Oxford
Alber, Mark malber@nd.edu Mathematics, University of California, Riverside
Alpar, Lale ela2120@columbia.edu Biological Sciences, Columbia University
Baker, Ruth ruth.baker@maths.ox.ac.uk Wolfson Centre for Mathematical Biology, Mathematical Institute, University of Oxford
Banwarth-Kuhn, Mikahl mbanw001@ucr.edu Mathematics, University of California, Riverside
Boareto, Marcelo marceloboareto@gmail.com BSSE, ETH Zurich
Briscoe, James james.briscoe@crick.ac.uk Developmental Dynamics, The Francis Crick Institute
Britton, Samuel sbrit004@ucr.edu Mathematics, University of California, Riverside
Buceta, Javier jab614@lehigh.edu Chemical and Biomolecular Engineering; Bioengineering Program, Lehigh University
Bush, Jeffrey jeffrey.bush@ucsf.edu Cell and Tissue Biology, University of California, San Francisco
Calvo, Juan juancalvo@ugr.es Matemática Aplicada, Universidad de Granada
Casares, Fernando fcasfer@upo.es Universidad Pablo de Olavide, Centro Andaluz de Biologia del Desarrollo
Chuong, Cheng-Ming cmchuong@usc.edu Keck School of Medicine, Dept. of Pathology, USC
Davidson, Lance lad43@pitt.edu Department of Bioengineering, University of Pittsburgh
Diego, Xavier xavier.diego@crg.eu Systems Biology, Center for Genomic Regulation (CRG)
Ericson, Johan Johan.Ericson@ki.se Cell and Molecular Biology, Karoliniska Institutet
Fletcher, Alexander a.g.fletcher@sheffield.ac.uk School of Mathematics and Statistics, University of Sheffield
Garikipati, Krishna krishna@umich.edu Mechanical Engineering, and Mathematics, University of Michigan
Germann, Philipp philipp.germann@crg.eu Systems Biology, Centre for Genomic Regulation, CRG
Gooch, Keith gooch.20@osu.edu Department of Biomedical Engineering, The Ohio State University
Goriely, Alain goriely@maths.ox.ac.uk Mathematics, University of Oxford
Gou, Jia jia.0415@gmail.com School of Mathematics, University of Minnesota
Govinder, Kesh govinder@ukzn.ac.za Mathematics, Statistics and Computer Science, University of KwaZulu-Natal
Green, Jeremy jeremy.green@kcl.ac.uk Dept of Craniofacial Development & Stem Cell Biology, King's College London
Han, Lifeng han@math.utah.edu Math, University of Utah
Hill, Nicholas Nicholas.Hill@glasgow.ac.uk School of Mathematics and Statistics, University of Glasgow
Hutson, Shane shane.hutson@vanderbilt.edu Physics & Astronomy, Biological Sciences, Vanderbilt University
Iber, Dagmar dagmar.iber@bsse.ethz.ch D-BSSE, ETH Zurich
Johnston, Laura lj180@columbia.edu Genetics and Development, Columbia University
KhudaBukhsh, Wasiur wasiur.khudabukhsh@bcs.tu-darmstadt.de Electrical Engineering and Information Technology, Technische Universität Darmstadt
Kulesa, Paul pmk@stowers.org Developmental Biology, Stowers Institute for Medical Research
Kumar, Bharat kumar.637@buckeyemail.osu.edu Biomedical Engineering, The Ohio State University
Lansford, Rusty lansford@usc.edu PIBBS, University of Southern California
Lawton, Andrew lawtona@mskcc.org Developmental Biology, Memorial Sloan-Kettering Cancer Center
Levy, Michael mglevy@berkeley.edu Biophysics Graduate Group, University of California, Berkeley
Lubkin, Sharon lubkin@ncsu.edu Mathematics, North Carolina State University
Maini, Philip maini@maths.ox.ac.uk Mathematical Institute, University of Oxford
Mao, Yanlan y.mao@ucl.ac.uk MRC LMCB, University College London
Marin-Riera, Miquel miquel.marinriera@helsinki.fi Centre of Excellence in Experimental and Computational Developmental Biology, University of Helsinki
Megason, Sean Sean_Megason@hms.harvard.edu Systems Biology, Harvard Medical School
Meinecke, Lina lina.meinecke@uci.edu Mathematics, UC Irvine
Nelson, Celeste celesten@Princeton.EDU Chemical & Biological Engineering, Princeton University
Nie, Qing qnie@math.uci.edu Biomedical Engineering & Mathematics, University of California, Irvine
Oates, Andrew andrew.oates@epfl.ch epfl, 'Ecole Polytechnique F'ed'erale de Lausanne (EPFL)
Othmer, Hans othmer@math.umn.edu School of Mathematics, University of Minnesota
Reilly, Matthew reilly.196@osu.edu Biomedical Engineering, The Ohio State University
Saiz Arenales, Nestor saizaren@mskcc.org Developmental Biology Program, Memorial Sloan-Kettering Cancer Center
Schneider, Richard Rich.Schneider@ucsf.edu Orthopaedic Surgery, University of California at San Francisco
Sharpe, James james.sharpe@crg.es Systems Biology, Centre for Genomic Regulation
Shi, Junping shij@math.wm.edu Mathematics, College of William and Mary
Shinbrot, Troy shinbrotkinetics@gmail.com Biomedical Engineering, Rutgers University
Sliwka, Piotr p.sliwka@uksw.edu.pl Faculty of Mathematics and Natural Sciences. School of Exact Sciences, Cardinal Stefan Wyszyński University
Tania, Nessy ntania@smith.edu Mathematics & Statistics, Smith College
Tsai, Kevin ytsai003@ucr.edu Mathematics, University of California, Riverside
Umulis, David dumulis@purdue.edu Ag. and Biological Engineering, Purdue University
Wu, Qiliang qwu@math.msu.edu Mathematics, Michigan State University
Xiong, Fengzhu fengzhu_xiong@hms.harvard.edu Genetics, Harvard Medical School
Zartman, Jeremiah jzartman@nd.edu Chemical and Biomolecular Engineering, University of Notre Dame
Zhang, Tongli tongli.zhang@uc.edu Molecular and Cellular Physiology, University of Cincinnati
Zheng, Xiaoming zheng1x@cmich.edu Mathematics, Central Michigan University
Cell biology processes: model building and validation using quantitative data

Cell biology processes such as motility, proliferation and death are essential to a host of phenomena such as development, wound healing and tumour invasion, and a huge number of different modelling approaches have been applied to study them. In this talk I will explore a suite of related models for the growth and invasion of cell populations. These models take into account different levels of detail on the spatial locations of cells and, as a result, their predictions can differ depending on the relative magnitudes of the various model parameters. To this end, I will discuss how one might determine the applicability of each of these models, and the extent to which inference techniques can be used to estimate their parameters, using both cell- and population-level quantitative data.

The growth and patterning of the vertebrate neural tube

The generation of the correct neuronal subtype at the appropriate position and time in the vertebrate neural tube is the first step in the assembly of functional neural circuits. It also represents one of the best-studied examples of embryonic pattern formation. Distinct neuronal subtypes are generated in a precise spatial order from progenitor cells according to their location along the anterior-posterior and dorsal-ventral axes. Underpinning this organization is a complex network of extrinsic and intrinsic factors. Particularly well understood is the mechanism that determines the generation of different neuronal subtypes in ventral regions of the spinal cord. In this region of the nervous system, the secreted protein Sonic Hedgehog (Shh) acts in graded fashion to organize the pattern of neurogenesis. This is a dynamic process in which increasing concentrations and durations of exposure to Shh generate neurons with successively more ventral identities. Interactions between the receiving cells and the graded signal underpin the mechanism of Shh action. In particular, the regulation of transcription factors induced or repressed by Shh signaling play an essential role in determining the graded response of cells. Thus the accurate patterning of the neural tube and the specification of motor neurons and the other neuronal subtypes characteristic of this region relies on the continuous processing and constant refinement of the cellular response to graded Shh signaling.

Eyes, large and small: variation of eye size in Drosophila and beyond.

Animals are characterized by their morphology –to such an extent that most often we recognize different species for their unique shape and size. Since organs are the product of development, mechanisms must exist to ensure the constancy of organ size and shape within a given species. However, these mechanisms need also to be plastic, as organ morphology has varied –and in some instances, very remarkably– during evolution. In the lab we investigate the mechanisms that regulate organ size by studying the eyes of flies. “Eyes� because they are specialized sensory structures of great biological relevance; and specifically “of flies� because eyes have undergone an extraordinary morphological and functional diversification within this huge insect group –the diptera. Typically, flies possess two eye types: small dorsal eyes (called “ocelli�) and large, lateral eyes. Although the development of both eye types is controlled by the same morphogen, Hedgehog (Hh), I will discuss the different strategies used by these two eye types to control their small or large size. I will further present work, that combines experimentation and mathematical modeling, aimed at identifying the changes in biological processes that might be responsible for the variation of eye size during evolution, and the limits to that variation.

The feather as a platform for mathematical modeling

The geometric forms and exquisite arrangement patterns of the feather provide a great opportunity for mathematical modeling. The accessibility for manipulation and imaging of cell behaviors in the relatively flat embryonic chicken skin allow experimental verification and identification of molecular basis of the modeling parameters. In the adult bird, feathers regenerate with distinct form, pigmentation, and arrangement, leading to the spectacular plumage patterns (Chuong and Richardson edit, 2009, Pattern Formation, IJDB). We have been using this multi-scale platform to collaborate with experts in mathematical modeling and have gained a deeper understanding of morphogenesis. Here are some examples we have done or are developing. 1. Periodic patterning involving Turing principles (Jung et al., 1998 DB; Maini et al.,2006, Science). 2. How collective cell behavior in developing skin that translate molecular signals into tissue patterns (Lin et al., 2009 DB; Model by Baker). Recent 4D imaging reveals even more complex behavior (ongoing). 3. Feather exhibits distinct branching forms: radial symmetry, bilateral symmetry, and bilateral symmetry in development and evolution (Li et al., Nat Comm, 2017; Model by Qing Nie). 4. Feathers exhibit pigment patterns with a feather (micro-patterning, Lin et al., 2013; Science) and across the body (Macro-patterning, ongoing). 5. In a feather tract (population), an intra-dermal muscle network is assembled using existing follicle as the reference points, and the network configuration is adaptable in respond to external stimuli (Wu et al., in prep; Model by Baker).

Cell-based modelling of epithelial morphogenesis

Embryonic epithelia achieve complex morphogenetic movements through the coordinated action and rearrangement of individual cells. In combination with experimental approaches, computational modelling can provide insight into these processes. In this talk I describe our application of vertex models, a widely-used class of computational model for epithelia, to investigate the role of patterned cell mechanics in two settings in the Drosophila embryo: tissue size control and convergent extension. I highlight the biological insights gained through this work and conclude by presenting some recent extensions to 3D morphogenesis.

Special Seminar: On Growth and Form and Mathematics: D'Arcy Thompson, 100 years on

TBD

A model for autonomous and non-autonomous effects of the Hippo pathway in Drosophila

While significant progress has been made toward understanding morphogen-mediated patterning in development from both the experimental and the theoretical side, the control of size and shape of tissues and organs is poorly understood. The Hippo pathway, which controls cell proliferation and apoptosis in Drosophila and mammalian cells, contains a core kinase mechanism that affects control of the cell cycle and growth. Studies involving over- and under-expression of components in the morphogen and Hippo pathways in Drosophila reveal conditions that lead to over- or undergrowth. We have developed a mathematical model that incorporates the current understanding of the Hippo signal transduction network and which can explain qualitatively both the observations on whole-disc manipulations and the results arising from mutant clones. We find that a number of non-intuitive experimental results can be explained by subtle changes in the balances between inputs to the Hippo pathway. Since signal transduction and growth control pathways are highly conserved across species, much of what is learned about Drosophila applies in higher organisms, and may have direct relevance to tumor dynamics in mammalian systems.

Beyond apical constriction: vertical telescoping and other novel models of epithelial bending

Epithelial bending is a fundamental process of developmental morphogenesis from the earliest stages of gastrulation to the final stages of organogenesis. Classically, epithelia bend by apical constriction in which apical actin contraction forces cells to become wedge-shaped. Established alternatives are “basal wedging” of the median hinge of the neural tube (in which wedge-shaped cells are formed by basal localization of nuclei and “bsal relaxation” in chick otic vesicle invagination and Drosophila leg folds (in which wedging occurs by basal expansion due to actin disassembly). We investigated invagination of epithelia to form tooth buds, hair follicles, and mammary ducts. We discovered that here cell wedging is driven cell-extrinsically by contraction of overlying (suprabasal) tissue in a thickening placode. In this “canopy contraction” mechanism, contractile force created by intercalation of suprabasal cells is transmitted to the basal lamina by apical protrusions of flanking “shoulder cells”. We found that, surprisingly, salivary glands (which are genetically closely related to tooth buds, hair follicles, etc.) invaginate without a suprabasal canopy and without cell wedging. Instead, cells shear vertically in an entirely novel process we call “vertical telescoping”. This vertical shear is driven by cells coordinately climbing over their more central basal neighbours by means of centripetally directed apical protrusions. Protrusion-driven cell shear unifies vertical telescoping with canopy contraction while explaining the different morphologies observed among a diverse family of epithelial invaginations. Modelling of adhesive interactions is underway.

Systems modeling of biochemical regulation and biomechanics in secondary palate fusion

Tissue fusion is a critical step in multiple examples of organogenesis, with its failure implicated in developmental defects ranging from cleft lip and palate to omphalocele (body wall) to hypospadias (urethra). To investigate how genetic and chemical perturbations disrupt tissue fusion, we have constructed a computational model of secondary palate fusion that incorporates cellular adhesion and viscoplasticity with paracrine/juxtacrine control of proliferation, apoptosis, EMT and cell migration. This model reproduces known genetic knockouts, known chronic chemical exposure effects, and serves as a platform for investigating responses to transient exposures and genetic determinants of differential chemical susceptibility.

Cell competition: a mechanism that promotes developmental stability

Development is a robust process that yields remarkably reproducible body size and bilaterally symmetric appendages. In Drosophila, developmental stability is tightly regulated and even small deviations from bilateral symmetry - known as fluctuating asymmetry (FA) - are quite rare. During growth, cells within organs behave as social communities and use comparisons of cell fitness to foster cooperation. Cells perceived as unfit are eliminated from the tissue via cell competition, which promotes precise organ size control and optimal organ fitness. Mutations in genes required for cell competition lead to loss of bilaterally symmetric wings, increasing wing FA. Dilp8 is a secreted peptide that via its neuronally expressed receptor, Lgr3, coordinates tissue growth with developmental timing by gating ecdysone production in the prothoracic gland. Loss of dilp8 or lgr3 leads to strong FA in adult wings, and also prevents cell competition. We will present results of experiments designed to reveal how Dilp8 and cell competition are functionally linked in a mechanism that promotes optimal animal fitness.

Direct and dynamic lineage analysis in amniote embryos
Getting in Shape: in vivo and in silico studies of tissue mechanics in growth control

How tissue size and shape are controlled is a fundamental biological question that remains remarkably ill understood. Using a combination of genetics, live imaging, experimental biophysics and computational modeling, we show that tissue mechanical forces can have an instrumental role in controlling cell shape patterns and cell division orientations. We show that differential proliferation rates can generate global patterns of mechanical tension to orient tissue growth in a self perpetuating and self organizing manner. These patterns of mechanical forces can also drive cytoskeletal rearrangements and 3D tissue morphogenesis.

Predicting principles of tissue growth and mechanics through the modelling of tooth morphogenesis

We want to understand the mechanisms that drive cell movement and tissue deformation during morphogenesis in order to predict how changes in development produce morphological variation that is relevant for evolution. We use the mammalian tooth as a model system due to the large variation it shows across the phylogenetic tree and its relatively well known development. Despite an extensive knowledge on the molecular pathways regulating the patterning and morphogenesis of the developing tooth, little is known about how individual cells move and what mechanisms are driving these movements. In order to shed light on those mechanisms, we design a mathematical model of tooth development in which cell movements are driven by compressive and tensile mechanical forces originating from tissue growth and cell-cell adhesion. The model is set to reproduce the transition between mouse molar bud (E13) and cap cap stages (E15), during which two epithelial folds protrude from the epithelial tooth germ and surround the underlying mesenchyme. When we fit the tissue specific growth rates in the model to the ones estimated from experimental data, the model correctly predicts the morphology of the tooth germ and the directionality of cell trajectories in the epithelial compartment. The model also predicts that different spatial patterns of mechanical forces arise when the adhesion strength between different cell types is varied. In order to validate the model predictions we experimentally infer the forces by means of mechanical perturbations on dissected tooth germs. We conclude that a simple model of differential growth and adhesion is able to explain the morphology, patterns of cell movement and partially the mechanical forces generated during tooth development. We argue that the addition of active cell migration might be required in order to improve the model predictions.

Size control of somites via a clock and scaled gradient

My lab combines in toto imaging in zebrafish embryos, with mathematical modeling, and molecular and mechanical perturbations to try to understand how groups of cells work together to form patterns and shapes. I will discuss three recent stories in my lab focussed on understanding how tissue/organ size is controlled. In the inner ear we find that size is primarily controlled by negative feedback between flux of fluid into the otic vessicle and hydrostatic pressure. For somites, we find that size is controlled by scaling of a molecular gradient. And in the neural tube we find that size is controlled based on mechanical feedback on differentiation rate.

Mechanics of epithelial morphogenesis

Cell-generated mechanical forces drive many of the tissue movements and rearrangements that are required to transform simple populations of cells into the complex three-dimensional geometries of mature organs. However, mechanical forces do not need to arise from active cellular movements. Here, I will describe recent studies that have illuminated the roles of passive mechanical forces resulting from mechanical instabilities between epithelial tissues and their surroundings. These mechanical instabilities cause essentially one-dimensional epithelial tubes and two-dimensional epithelial sheets to buckle or wrinkle into complex topologies containing loops, folds, and undulations in organs as diverse as the brain, the intestine, and the lung. Our work suggests a new class of tissue development - buckling or wrinkling morphogenesis - and that this morphogenetic mechanism may be broadly responsible for sculpting organ form. Harnassing these mechanical instabilities represents an intriguing strategy for engineering organs ex vivo.

Data-driven multiscale and stochastic modeling of cell fate dynamics in tissue growth

In tissue growth and morphogenesis, cells make fate decisions in response to different and dynamic environmental and pathological stimuli. Recently, there has been an explosion of experimental data at various biological scales, including gene expression and epigenetic measurements at the single cell level. While such data provide some details related to cellular states at a particular scale, many gaps remain in our knowledge and understanding of how cells make their dynamic and spatial decisions in tissue growth. Here we present multiscale and stochastic models in analyzing single-cell molecular data and their connections with spatial tissue dynamics. Our approach requires development of new mathematical and computational tools in machine learning, stochastic analysis and simulations, and PDEs with moving boundaries. We will use our data-driven multiscale approach to delineate several novel mechanisms or principles underlining spatial cell fate dynamics in development and regeneration.

Period and Pattern in the Embryo

The segmentation clock is a multi-cellular patterning system of genetic oscillators thought to control the rhythmic and sequential formation of the vertebrate embryo's body segments. Individual oscillating cells are synchronized with their neighbors, forming a coherent wave pattern of gene expression. How these wave patterns arise and how they are regulated during embryogenesis is not clear. I will describe recent progress in understanding the behavior of individual cells as they slow their oscillations and differentiate during segmentation, and discuss how this gives rise to the tissue-level wave patterns.

Models of Cell Motility

We will discuss how mechanics and signaling can be incorporated in cell-based models and used in a variety of contexts, including tissue growth and cell movement.

Developmental Mechanisms Underlying the Evolution of Form and Function in the Jaw

How does form arise during development and change during evolution? How does form relate to function, and in particular, what processes allow structures of embryos to presage their later use in adults? To address these questions, we perform experiments that leverage the distinct jaw anatomies of duck and quail. Much like that found in humans, duck develop a pronounced secondary cartilage at the tendon insertion of their jaw adductor muscle on the coronoid process of the mandible. An equivalent secondary cartilage is absent in quail and other species such as mice. We focus on the role of neural crest mesenchyme (NCM), which produces all the cartilages and bones in the jaw skeleton. NCM also makes muscle connective tissues including ligaments and tendons. In contrast, jaw muscles are derived from mesoderm. Transplanting NCM from quail to duck generates quail-like pattern in the jaw skeleton and accompanying musculature, which in turn causes a loss of secondary cartilage on the coronoid process. Moreover, paralyzing muscle or blocking Transforming Growth Factor-Beta (TGFb) and Fibroblast Growth Factor (FGF) signaling also inhibits secondary chondrogenesis on the coronoid process. Thus, we hypothesize that species-specific differences in TGFb and FGF signaling, jaw architecture, and mechanical forces promote formation of secondary cartilage on the coronoid process of duck versus quail. We test this hypothesis by evaluating the extent to which TGFb and FGF signaling are NCM-mediated, and we use loss-of-function approaches to determine precisely when and where these pathways induce secondary cartilage at the coronoid process. We also investigate the link between jaw architecture and mechanical forces at the mandibular adductor using 3D reconstructions and a finite element model. Additionally, we block mechanotransduction to understand how the local mechanical environment regulates molecular programs for secondary cartilage. By investigating the effects of NCM-mediated signaling, musculoskeletal anatomy, and mechanical forces on the induction of secondary cartilage, this work offers insights mechanisms that link form and function during development and evolution.

The relationship between growth and form in the developing limb bud

The vertebrate limb bud is a classical model system for developmental biology – with the advantage of having been studied for many decades. Despite this, and despite its relatively simple shape, a consensus model of its physical morphogenesis has not been reached. I will introduce our own hypothesis on limb bud morphogenesis, and contrast it to previous ideas. I will introduce our 3D dynamical model which captures this hypothesis (a Cellular Potts Model) and also discuss a key theme of this workshop – how to get the right balance in course-graining a model: too many details or too few?

Cellular Morphogenesis in Silico

Recent advances in the in silico modeling of cellular dynamics now permit explicit analysis of cellular structure formation. This provides the scientific community with the capability of testing hypotheses in precisely controlled environments for the first time. We describe an agent-based approach that simulates cells that reproduce, migrate and change shape. We find that both expected morphologies and previously unreported patterns spontaneously self-assemble. Most of the states found computationally have been observed in vitro, and it remains to be established what role these self-assembled states may play in in vivo morphogenesis.

Mathematical modeling and image analysis of BMP-mediated patterning in developing zebrafish embryos

Bone Morphogenetic Proteins (BMPs) act in developmental pattern formation as a paradigm of extracellular information that is passed from an extracellular morphogen to cells that process the information and differentiate into distinct cell types based on the morphogen level. Numerous extracellular modulators and feedback regulators establish and control the BMP signaling distribution along the dorsal-ventral (DV) embryonic axis in vertebrates to induce space and time-dependent patterns of gene expression. To identify how the dynamic pattern is regulated during development, we have developed a seamless data-to-model integration and optimization strategy. First, the nuclear intensities of fluorescent stained Phosphorylated-Smad5 (P-Smad) are acquired for each nuclei in each embryo from staged populations to provide a quantitative time-course for the BMP signaling gradient. Next, the nuclei are segmented to yield quantitative point-clouds of P-Smad level at each nuclei. The individual point clouds are registered to similarly staged embryos using a process called Coherent Point Drift (CPD) and the registered populations provide rigorous quantification of BMP signaling. To delineate the mechanism of BMP signal inhibition by the secreted binding proteins Chordin (Chd), and Noggin (Nog) a mathematical model was developed and optimized against the population data for wild type and Chd mutants. The results of the data-driven computational model will be presented.

Mechanical coupling coordinates the co-elongation of axial and paraxial tissues

The embryonic body axis is composed of tissues that elongate at the same pace despite exhibiting strikingly different cellular organization. Whether their co-elongation is coordinated remains unclear. Here we report evidence of mechanical coupling between axial and paraxial tissues. Combining microsurgery and live-imaging in avian embryos, we found that the presomitic mesoderm (PSM) compresses the neural tube and notochord promoting their convergence and elongation. Computational simulation predicts cell motility in the PSM to generate compression that causes axial tissues to push the caudal progenitor domain, which we tested experimentally. Surprisingly, this axial push is in turn required for the progenitor addition that sustains PSM growth. Together our results show that forces produced by collective cell dynamics couple different elongating tissues into an engine-like positive feedback loop.

Tissue-level communication through patterning of intercellular calcium wave dynamics

Identification of the cell-cell communication mechanisms that integrate information at multiple hierarchical scales from cells to the whole organism is a grand challenge for developmental biology with broad implications in regenerative medicine. In particular, how some organs can recover from wounding and repair tissue patterning is still largely a mystery. One critical component during wound healing and regeneration is the regulation of calcium (Ca2+) ions, which are second messengers that integrate information from multiple signaling pathways. Here we characterize periodic intercellular Ca2+ waves (ICWs) in a model organ system of epithelial growth and patterning—the Drosophila wing imaginal disc. We developed a novel regulated environment for micro-organs (REM-Chip) device that enable a broad range of genetic, chemical and mechanical perturbations during live imaging and have created an image processing pipeline to analyze Ca2+ dynamics. We propose that the patterning of ICWs reflects underlying morphogenetic patterning of developing tissues and that the ICWs provide information transmission between compartments within the organ. Long distance communication networks through gap junctions thus could provide a general physiological-based mechanism for coordinating cellular activity in epithelial tissues during development and wound healing. Thus, integrative mechanistic insights into the cross-talk between Ca2+ and morphogen signaling pathways have a broad range of potential medical applications including for diagnostics and therapeutics. Long-term efforts are focused on developing integrative predictive models that connect Ca2+ signaling dynamics to cell and tissue mechanical properties.

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Cellular Morphogenesis in Silico
Troy Shinbrot

Recent advances in the in silico modeling of cellular dynamics now permit explicit analysis of cellular structure formation. This provides the scientific community with the capability of testing hypotheses in precisely controlled environments for

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Cell-based modelling of epithelial morphogenesis
Alexander Fletcher

Embryonic epithelia achieve complex morphogenetic movements through the coordinated action and rearrangement of individual cells. In combination with experimental approaches, computational modelling can provide insight into these processes.

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Predicting principles of tissue growth and mechanics through the modelling of tooth morphogenesis
Miquel Marin-Riera

We want to understand the mechanisms that drive cell movement and tissue deformation during morphogenesis in order to predict how changes in development produce morphological variation that is relevant for evolution. We use the mammalian too

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Mechanical coupling coordinates the co-elongation of axial and paraxial tissues
Fengzhu Xiong

The embryonic body axis is composed of tissues that elongate at the same pace despite exhibiting strikingly different cellular organization. Whether their co-elongation is coordinated remains unclear. Here we report evidence of mechanical coupling

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Models of Cell Motility
Hans Othmer

We will discuss how mechanics and signaling can be incorporated in cell-based models and used in a variety of contexts, including tissue growth and cell movement.