Past talks

Lent Term 2021

18/01/21 – Anna Erzberger (EMBL, Heidelberg) 

First a war then a dance: How sensory organs take shape

Actively regulated symmetry breaking, which is ubiquitous in biological cells, underlies phenomena such as directed cellular movement and morphological polarization. Here, we investigate how an organ-level polarity pattern emerges through symmetry breaking at the cellular level during the formation of a mechanosensory organ. Combining theory, genetic perturbations and in vivo imaging, we study the development and regeneration of the fluid-motion sensors in the zebrafish’s lateral line. We find that two interacting symmetry-breaking events—one mediated by biochemical signalling and the other by cellular mechanics—give rise to precise rotations of cell pairs, which produce a mirror-symmetric polarity pattern in the receptor organ. 

25/01/21 – Nicolas Minc (IJM, Paris)

Cell shape, cell division and the development of early embryos

Life for all animals starts with the fertilization of the egg, followed by the centration of the sperm nucleus and a 3D-choreography of reductive cell divisions called cleavage patterns. These invariant morphogenetic processes rely on the precise motion, positioning and orientation of large microtubule (MT) asters which grow out from centrosomes around nuclei and spindles. Using a combination of mathematical models, in situ force measurement and quantitative imaging in large marine embryos, we demonstrate that the geometry of eggs and blastomeres may largely influence these early morphogenetic events. Our data support that dynein-dependent MT cytoplasmic pulling forces that scale to MT length may function as a general design to convert cell shape into net aster force, torques and consequent motion, position and orientation. This design allows to account for the centration of sperm nuclei at fertilization, competition between symmetric and asymmetric divisions, as well as the geometry of cleavage patterns in multiple invertebrate and vertebrate species. These studies unravel the default self-organization rules governing division positioning and early embryogenesis 

01/02/21 – Magali Suzanne (CBI, Toulouse)

From cell dynamics to robust tissue folding 

Mechanical forces are critical regulators of cell shape changes and tissue remodelling during developmental morphogenetic processes. Recently, we revealed that apoptotic cells, far from being eliminated passively, are generating apico-basal forces that constitute an important mechanical signal involved in epithelial folding in the developing leg of Drosophila. Here, I will present more recent works, based on this initial discovery regarding the cellular mechanism responsible for force generation in apoptotic cells and the potential conservation of this mechanism in vertebrate. I will further discuss the surprising similarities of the mechanical impact of apoptotic cells to the one of ingressing cells undergoing EMT on tissue remodelling. Finally, I will present data regarding the mechanics of morphogenesis robustness involving Myosin II planar polarity and the Arp2/3 complex. 

08/02/21 – Caren Norden (IGS, Oeiras)

Generating order out of (pseudo)chaos during vertebrate retinal lamination

One important question in developmental neurobiology is how collective cell behaviour ensures the reproducible formation of a healthy and functional brain. We explore this question using the vertebrate retina as a model tissue. The retina is the part of the central nervous system dedicated to transmit visual information from the environment to the brain. The mature retina consists of five main types of neurons in defined laminae giving the whole organ a structured appearance. This neuronal lamination pattern is strikingly conserved between vertebrates including humans. A recent focus of our work is to understand how this laminated structure arises reproducibly. In the retina, in contrast to other parts of the brain, growth and neuronal lamination occur in parallel. This means that proliferation and neuronal migration need to be coordinated to ensure the continued generation of progenitors while at the same time enable neuronal positioning. Using long term imaging by light sheet microscopy in combination with quantitative image analysis we explore the interplay of these phenomena for different neuronal cell types. Overall, the understanding the positioning of different neuronal cell types in the context of general tissue development will contribute to detangle the complex, multi-scale event of retinogenesis. This in turn will generate insights on the reproducible generation of complex including the intriguing brain. 

15/02/21 – Charlotte Kirchhelle (University of Oxford)

The importance of being edgy: directional growth control in Arabidopsis lateral roots”

A fundamental question in biology is how multicellular organisms robustly produce organ shapes. The underlying process of morphogenesis involves the integration of biochemical, genetic, and mechanical factors across multiple spatio-temporal scales. In plants, morphogenesis is dominated by the rigid cell wall, which fixes cells in their position. Adjacent cells must therefore coordinate their growth patterns, which are in turn controlled by the mechanical properties of the cell wall. Cell walls are assembled by a complex intracellular trafficking machinery that delivers cell wall components and their associated biosynthetic machinery to different subcellular regions. We have recently discovered that a trafficking route directed to cell edges is essential for cell wall assembly and directional growth at the cell and organ scale. Edge-based growth regulation is independent of oriented cellulose deposition, the central paradigm of directional growth control in plants. Based on our latest data, we now propose that morphogenesis is controlled by a signalling module at cell edges which integrates feedback from the cell wall. We propose that a receptor-like protein recently identified as the first known cargo of edge-directed trafficking acts as a core component of a cell wall signalling module at edges. This hypothesis provides a mechanistic explanation for the role of cell edges as integrators of cell and tissue-level mechanical factors into coordinated cell wall assembly. 

22/02/21 – Eva Pillai (University of Cambridge)

Two signals converge on a nerve cell’s path: The interplay between chemical and mechanical signals in the developing brain

During nervous system development, growing neurons respond to mechanical as well as chemical signals in their environment. How these different signals interact, to guide neurons to their end target, is currently poorly understood. We found that retinal ganglion cell axons grow along stiffness gradients in the developing Xenopus brain. Mechanosensitive ion channels (MSCs) are key players in transducing these mechanical cues into intracellular signals. Pharmacological blocking of MSCs and knockdown of the MSC, Piezo1, caused severe pathfinding errors in vivo. In addition to directly impacting axon growth, downregulation of Piezo1 also dramatically altered the expression of semaphorin3A (Sema3A), a chemical guidance cue known to be critical in axon pathfinding. While Piezo1 knockdown softened brain tissue, knockdown of Sema3A did not alter brain mechanics. Sema3A-producing neuroepithelial cells grown on substrates of varying stiffness adapted expression levels of Sema3A to their mechanical environment. Our results thus indicate that the expression of signalling molecules may be modulated by tissue mechanics, which has important implications given that tissue stiffness changes throughout development as well as during ageing and disease. 

01/03/21 – Olivier Ali (ENS, Lyon)

Against the grain; Modeling seed growth control as an mechano-sensitive incoherent feedforward loop

Mechanical stresses arising in growing tissues are key regulators of morphogenesis. This is especially true in plants where the cell wall assembly constitutes the main load-bearing structure. Its mechanical sollicitation, due to internal cell turgor, triggers two main antagonist responses: wall stiffening and cell expansion. From asystematic perspective, these two mechanisms constitute an incoherent feedforward loop. Within biochemical regulatory networks, such motifs may act as oriented triggers or pulse generators. However,their involvement in mechano-sensitive pathways is less common and understood. What are the properties of mechano-sensitive incoherent feedforward loop (ms-IFFL)? To what extent are plant morphodynamics influenced by them? The simple shape and “russian doll” organization of the Arabidopsis thaliana seed offer unique conditions toaddress these questions. From quantitative experiments we derived a 1D “toy model“ to investigate the ms-IFFL properties. This model accounts for seed morphodynamics in wild-type and mutant populations and sheds new light on the counter-intuitive role of pressure in growing plant tissues. 

08/03/21 – Buzz Baum (LMB, Cambridge)

The evolution of cell division: from archaea to eukaryotes 

“Living systems propagate by undergoing rounds of cell growth and division. In fact, all modern day organisms are the progeny of a single cell that divided over 3.5 billion years ago. In this talk, by looking at features of the cell division machinery that we (eukaryotes) share with our cellular relatives, the archaea, we will attempt to shed light on the origins of our cell division machinery. In addition, by studying cell division in Sulfolobus, a member of the TACK/Asgard archaea, we will ask whether it is possible to use these relatively simple organisms to reveal fundamental features of the process of cell division that are hard to discern in our cells because of their complexity.” 

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Easter Term 2021

24/04/2021 – Elias Barriga (IGS, Oeiras)

Fine-tuning cell mechanics at the onset of collective cell motion

The synchronisation of major morphogenetic events such as collective cell migration (CCM) has been recently shown to emerge from the mechanical interaction between tissues. Yet, whether interacting tissues balance their elastic properties and the molecular mechanism that mediates this process remains unclear. To address this, we explored the recently established mechanical interplay between neural crest (NCs), a mechanosensitive cell population and its migratory substrate, the mesoderm. Combining in vivo experiments with biophysical and theoretical approaches we revealed that NC and mesoderm tend to match their elastic properties over time leading to NCs fluidisation and CCM. Strikingly, NCs fluidisation is fine-tuned by microtubule acetylation via a novel mechanosensitive pathway involving Piezo1 regulation of the de-acetylase Hdac6. Overall, our data positions microtubule de-acetylation as a key mediator of the mechanomolecular feedback-loops that synchronise morphogenetic events. 

04/05/2021 – Yuling Jiao (IGDB CEPEI, Beijing)

Stochastic gene expression drives mesophyll protoplast regeneration

Cell pluripotency is fundamental to biology. It has long been known that differentiated somatic plant cells may reacquire pluripotency, but the underlying mechanism remains elusive. In many plant species, a single isolated mesophyll protoplast may regenerate into an entire plant, which is widely used in gene transformation. Here, we identified two transcription factors whose ectopic activation promotes protoplast regeneration. Furthermore, we found that their expression was induced by isolating protoplasts but at a very low frequency. Using live-imaging and single-cell transcriptomics, we show that isolating protoplasts induces enhanced expression variation at the genome level. Isolating protoplasts also leads to genome-wide increases in chromatin accessibility, which promotes stochastic activation of gene expression and enhances protoplast regeneration. We propose that transcriptome chaos with increased expression variability among cells creates a cellular-level evolutionary driver selecting for regenerating cells.

10/05/2021 – Sally Horne-Badovinac (University of Chicago)

Wisdom of the crowd – Mechanisms that coordinate individual cell movements for epithelial migration

The collective migration of epithelial cells underlies tissue remodelling events associated with morphogenesis, intestinal turnover, wound repair, and cancer. For an epithelium to migrate in a directed way, the cytoskeletal machinery that powers each cell’s motility must become aligned in the direction of tissue movement. Using the follicular epithelium of Drosophila, my lab studies how this tissue-level alignment is achieved. In the first part of the talk, I will discuss our work on a planar signalling system that determines where leading-edge protrusions form in each cell, as well as our efforts to understand how these initially local signals are propagated to polarize the epithelium for directed migration. In the second part of the talk, I will discuss how a parallel array of stress fibres at each cell’s basal surface may reinforce collective migration by ensuring that all the cells in the tissue maintain a linear trajectory. 

17/05/2021 – Jochen Rink (MPI BPC, Göttingen)

Size sensing in biological systems – new insights from planarians

Planarians are remarkable animals. They can regenerate from tiny tissue pieces, maintain continuous cell turn over via abundant pluripotent stem cells and continuously grow or literally shrink their bodies in a food-supply dependent manner. Such astonishing adult size plasticity is accompanied by the size dependence of multiple aspects of planarian physiology, including the organismal growth and de-growth rates, levels of metabolic energy stores or the formation of the reproductive system at a precise size threshold. This implies the existence of mechanisms that sense system size and elicit size-dependent physiological changes, the elucidation of which is a long-standing goal of my laboratory. My talk will present recent findings, including direct size-dependencies in planarian gene expression, their upstream control via a size dependent hormone and downstream functional consequences. Our results thus far suggest the existence of magnigens, the levels of which encode system size and that, via dose-dependent effects on target gene expression, tune physiology to the momentary size of the animal.

24/05/21 – Matteo Mole (Babraham institute, Cambridge)

Morphogenesis of the mouse and human embryo beyond implantation

During the transition from pre-implantation to early post-implantation the mammalian embryo undergoes major morphogenetic changes, leading to transformation of the blastocyst into the egg-cylinder or bilaminar disk configuration, in mouse or human respectively. We found that integrin b1 is required during this transition, coordinating morphogenesis and promoting survival of the embryo proper. By single cell RNAseq, we also characterised a sequence of events underlying post-implantation development of the human embryo. We identified a group of cells which may act as an evolutionary-conserved anteriorising signalling centre for the establishment of the anterior-posterior axis prior to gastrulation. 

01/06/21 – Henrik Åhl (SLCU, Cambridge)

Regulation of Phyllotaxis by Auxin Transport Proteins

Plants rely on local accumulation of the phytohormone auxin for a wide range of processes crucial for functional development. In the plant shoot, local auxin maxima specify initiation sites for new organs, such as flowers. Active transport of auxin by PIN proteins, which polarise on cell membranes, is a primary driver for the formation of auxin maxima, but the intricacies of PIN-mediated auxin transport is not fully understood. To this end, we have combined computational and experimental approaches to quantitatively assess the cellular abundance and polarity patterning of the auxin efflux carrier PIN1, as well as the resulting auxin pattern following comprehensive simulations of auxin transport as mediated by active and passive transport mechanisms. We find that our PIN1 has strong abundance and polarity patterning correlating strongly with the developmental stage of establishing primordia, both in the epidermis and provasculature. Further, our model suggests that resulting local PIN1 and auxin maxima have shifted profiles relative to the developmental stage of the corresponding primordium, implicating a time-scale for PIN1-auxin feedback coupling. In addition, we analyse the patterning of auxin in meristems with computationally modified patterning of auxin transport proteins, and provide patterning-based explanatory mechanisms for experimentally observed phenotypes. Lastly, we correlate the geometric properties of cells with the output of our analysis and model, linking the timing of local maxima in the shoot to the development of morphologically relevant cellular features.

01/06/21 – Susie McLaren (Gurdon Institute, Cambridge)

Stretching out the embryo – Anterior expansion and posterior addition to the notochord mechanically coordinate embryo axis elongation

During development the embryo body progressively elongates from head-to-tail along the anterior-posterior (AP) axis. We investigated how the morphogenesis of one tissue can physically deform its neighbouring tissues to contribute to axis elongation. The rod-shaped notochord runs through the middle of the embryo and is flanked on either side by the somites in the segmented region of the axis and presomitic mesoderm in the posterior. Cells in the notochord undergo an expansion that is constrained by a stiff sheath of extracellular matrix, leading to an increase in notochord stiffness as the embryo develops – making it a candidate for driving the physical deformation of surrounding somitic tissue. Using multi-photon mediated cell ablation, we removed specific regions of the developing notochord and quantified the impact on axis elongation. We show that anterior notochord cell expansion generates a force that displaces notochord cells posteriorly and contributes to the elongation of segmented tissue during post-tailbud stages of development. Crucially, unexpanded cells derived from posterior progenitors provide resistance to anterior notochord cell expansion, allowing for force generation across the AP axis. Therefore, notochord cell expansion and addition of cells to the posterior notochord act as temporally coordinated morphogenetic events that elongate the zebrafish embryo AP axis.  

07/06/21 – Buffy Eldridge-Thomas (PDN, University of Cambridge)

Investigating the role of Syndecan, a conserved heparan sulphate proteoglycan, in the maintenance and proliferation of progenitor cells in the adult Drosophila midgut

The stem cell niche is a complex microenvironment which regulates stem cell behaviour through secreted, cell-cell contact and mechanical cues. An under-studied component of epithelial stem cell niches is the basement membrane, a thin, laminar structure to which cells adhere basally via adhesion receptors, including Integrins, Dystroglycan and Syndecan. Using the adult Drosophila midgut as a model system to investigate the role of adhesion receptors in directing progenitor cell behaviour in vivo, we identified the laminin receptor Syndecan as a regulator of tissue renewal. Syndecan knockdown causes progenitor cells to detach from the basement membrane and be lost from the intestinal epithelium. Interestingly, progenitor depletion does not lead to major tissue attrition over time but to retention of old differentiated cells for longer periods. Whilst this preserves tissue integrity in the short term, it could potentially have deleterious effects as old cells accumulate mutations or become damaged by local insults. To reveal how Syndecan contributes to progenitor maintenance and communication with neighbouring cells, our ongoing work investigates what subset of progenitors depend on Syndecan activity, and which signalling pathways become disrupted in its absence.  

07/06/21 – Toby Andrews (FCI, London)

Single-cell morphometrics reveals ancestral principles of notochord development

Embryonic tissues are sculpted by the dynamic behaviours of their constituent cells. In turn, evolutionary transitions in form arise from tweaks in those behaviours. To define how evolution acts on developmental programmes, new methods are needed to map out morphogenesis across a diversity of organisms, including non-model systems where experimental traction is limited. Here, we have applied a quantitative approach to define how the notochord forms during the development of amphioxus – a basally-branching chordate, used to infer ancestral properties in the phylum. Using a single-cell morphometrics pipeline, we quantify the geometries of thousands of amphioxus notochord cells, and project them into a morphospace, in which they organise into branching trajectories of cell shape change. Focussing on a single region, we first define stepwise cell shape transitions that enforce a constant rate of tissue elongation in the notochord. Within this, we use mathematical modelling to predict a synergistic relationship between intercalation and growth in generating length. By spatially mapping trajectories, we go on to identify conspicuous regional variation, both in developmental timing and trajectory topology. Finally, we show experimentally that posterior cell division modulates notochord length by regulating the number of cells entering each shape trajectory. Our approach offers a new way of seeing in the study of tissue morphogenesis, that enables holistic analysis of cell behaviours defining tissue geometry. It also reveals an unexpectedly complex scheme of notochord morphogenesis that might have operated in the first chordates.

14/06/21 – Rashmi Priya (FCI, London)

Building organs – emergence of form and fate through local force imbalance

How diverse cell fates and complex forms emerge and interact across scales during organogenesis remains unknown. A critical step during vertebrate heart development is trabeculation, during which the primitive heart transforms from a simple epithelium to an intricate topological structure consisting of two distinct cell types – outer compact and inner trabecular layer cardiomyocytes (CMs). Trabeculation defects cause cardiomyopathies and embryonic lethality, yet how tissue symmetry is broken to specify trabecular CMs is unknown. We now report that local tension heterogeneity drives organ-scale patterning and cell fate decisions during zebrafish cardiac trabeculation. Tissue-scale crowding induces local differences in CM contractility, which subsequently triggers stochastic delamination of CMs from the outer compact layer to seed the inner trabecular layer. CMs with higher contractility delaminate, even in the absence of critical biochemical regulators (Nrg/Erbb2) to seed the trabecular layer. Notably, mechanics direct CM fate specification, as mechanical segregation of CMs into compact versus trabecular layer is sufficient to induce differential Notch activity and apicobasal polarity. Notch in turn suppresses CM actomyosin machinery to limit excessive delamination, thereby preserving the myocardial wall architecture. Thus, multiscale synergistic interactions between mechanical forces and cell fate ensures robust self-organized organ patterning.

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Michaelmas Term 2021

11/10/21 – Maria Leptin (EMBL, Heidelberg)

Cell shape determination: Mechanical competition vs. endogenous genetic programme 
The intrinsic genetic programme of a cell is not sufficient to explain all of the cell’s activities. External mechanical stimuli are increasingly recognized as determinants of cell behaviour. In the epithelial folding event that constitutes the beginning of gastrulation in Drosophila, the genetic programme of the future mesoderm leads to the establishment of a contractile actomyosin network that triggers apical constriction of cells, and thereby, tissue folding. However, some cells do not constrict but instead stretch, even though they share the same genetic programme as their constricting neighbours. We show here that tissue-wide interactions force these cells to expand even when an otherwise sufficient amount of apical, active actomyosin is present. Models based on contractile forces and linear stress-strain responses do not reproduce experimental observations, but simulations in which cells behave as ductile materials with non-linear mechanical properties do. Our models show that this behaviour is a general emergent property of actomyosin networks in a supracellular context, in accordance with our experimental observations of actin reorganisation within stretching cells. 

18/10/21 – Jing Yan (Yale University)

Morphogenesis and cell ordering in bacterial biofilms  

Biofilms, surface‐attached communities of bacterial cells, are a concern in health and in industrial operations because of persistent infections, clogging of flows, and surface fouling. In this talk, I will discuss about our recent progress in using Vibrio cholerae as a model biofilm former to reveal the mechanical principles behind biofilm formation, both at the single cell level and at the continuum level. I will first present a new methodology to image living, growing bacterial biofilms at single-cell resolution, and demonstrate how cell-to-surface adhesion and growth-induced flow together drive a collective cell reorientation cascade in V. cholerae biofilms. Next, I will demonstrate how external confinement profoundly changes the morphogenesis pathway and cellular organization inside a biofilm. Finally, I will delve into the molecular mechanisms underlying V. cholerae adhesion and biofilm development.   

25/10/21 – Renske Vroomans (SLCU, Cambridge)

Evolution of selfish multicellularity: changes in gene regulation at the origin of multicellularity 

Most multicellular organisms undergo some form of development and morphogenesis. Recent studies have shown that many of the genetic tools to regulate these processes were already present in their unicellular ancestor. This suggests that the most ubiquitous developmental processes may also be traced back all the way to the emergence of multicellularity itself. Furthermore, the evolutionary transition to multicellularity may have predominantly required changes in regulation and coordination, more than changing the gene content. We use evolutionary models to study the evolution of cell adhesion and gene regulation at the onset of multicellularity. We find that the physical properties of cell clusters can be sufficient to drive selection for cell adhesion. Once cells evolve adhesion however, their regulatory dynamics evolve as well: while cells evolve adhesion to survive collectively, within such cohesive clusters, intercellular competition drives cells to behave “selfishly” by dividing sooner and perform the collective task later. The model demonstrates how the transition to multicellularity may have driven a drastic switch in cell behaviour, leading to complex coordinated dynamics compared to the unicellular cousins, without changing the genetic toolkit. 

25/10/21 – Mateusz Trylinski (LMB, Cambridge)

Insights into the mechanism and evolution of glial ensheathment  

Coordination of cellular behaviours enables both the formation of tissues and complex organs during development and the appearance of new structures during evolution. One of such events is the emergence of glial wrapping during Metazoan history, which among others increased the speed and the precision of information transfer along axons. Although we have a good understanding on the current mechanisms regulating this process, little is known about their evolutionary origin.  Here, we address this question by using an evolutionary-conserved sensory organ, the Drosophila thoracic microchaete. These organs are made of four lineage-related cells – two outer structural cells and two inner sensory cells – that are organised in a concentric, or “onion-like”, fashion. Given that homologous structures can be found in Tardigrades, which have diverged from Arthropods over 500 million years ago, we speculate that the mechanisms involved in the successive ensheathments during microchaete morphogenesis might be reminiscent of the ancestral state.  In particular, we investigate how, following the first lineage division that gives rise to the outer-cell and inner-cell progenitors, the future structural-sensory interface is generated, and how the inner-cell progenitor is enwrapped by the outer-cell progenitor. Our preliminary results suggest that this wrapping event combines both non-transcriptional effectors related to asymmetric cell division and transcriptional targets expressed by the inner-cell progenitor. 

08/11/21 – Ben Steventon (Genetics Department, Cambridge)

Integrating pattern formation and cell movements in our understanding of morphogenesis

As cells proceed through development, information contained in the genome is expressed in a context-dependent manner. This must be regulated precisely in both space and time to generate patterns of gene expression that set-up the spatial coordinates of tissue and organ primordia that build the embryo. Our current understanding of pattern formation relies on the concept of positional information, the idea that cells receive instructive signals that impart a spatial coordinate system to generate pattern. While this model works very well in static cell populations with minimal cell rearrangement, it becomes challenging when considering dynamic morphogenetic processes such as gastrulation. Furthermore, pattern formation in gastrulation is highly flexible to alterations in the size, scale and spatial rearrangement of cells in both experimental and evolutionary situations.  Our work seeks to provide illustrations of two concepts that will help resolve these long-standing problems of pattern regulation, evolvability and self-organisation. Firstly, downward causation emphasises the role that multi-tissue interactions play in relaying information from changes at the organ and organism level to the regulation of gene regulatory networks (GRNs) at the cell level. Secondly, pattern emergence considers how extracellular signals act to control the dynamics of autonomous GRN activity, rather than as instructive signals to direct cell fate transitions. In this sense, we propose that pattern formation should not be seen as a downstream output of organisers and their responding tissues, but rather as an emergent property of their dynamic interaction. 

08/11/21 – Jamie McGinn (Stem Cell Institute, Cambridge)

A biomechanical switch regulates the transition towards homeostasis in oesophageal epithelium 

Mounting evidence suggests that epithelial stem cells are more dynamic than originally thought. Stem cell behaviour is not a discrete state as it can be re-gained by differentiating cells as a result of tissue challenges such as injury and tumorigenesis. This plasticity may explain why, despite decades of intensive research in epithelial stem cell biology, the field still debates about the identity of the cell populations contributing to the homeostasis and repair of squamous tissues. In order to fully unveil the rules governing epithelial cell behaviour, it is critical to understand the dynamic nature of epithelial cells by exploring their response to situations away from homeostasis. In this study we investigate the cell fate transitions taking place in the mouse squamous oesophageal epithelium from birth until the onset of adult homeostasis, as a physiological model of rapid but restricted tissue growth. Observations throughout post-natal development show that oesophageal expansion after birth occurs in a biphasic pattern, with a fast initial growth that slows down before reaching adult tissue size. This turning point is characterized by a range of changes in the expression of key developmental factors, defining the transition of cell fate identity in the basal progenitor cell compartment. The establishment of homeostatic oesophageal features coincide with significant changes in tissue architecture, including tissue strain and decreased cell density. Remarkably, tissue stretching experiments reveal that the mechanical changes experienced by the developing oesophageal epithelium after birth are critical for shifting the rapid growing tissue into a homeostatic mode. 

15/11/21 – Bertrand Benazeraf (Université Toulouse 3)

To stay or leave? Cell-to-cell heterogeneity and progenitor’s segregation within the bird embryonic tail 

Although cell-to-cell heterogeneity in gene and protein expression within cell populations has been widely documented, we know little about its biological functions. By studying progenitors of the posterior region of bird embryos, we found that expression levels of transcription factors Sox2 and Bra, respectively involved in neural tube and mesoderm specification, display a high degree of cell-to-cell heterogeneity. By combining forced expression, and downregulation approaches with time-lapse imaging we demonstrate that Sox2-to-Bra ratio guides progenitor’s motility and their ability to stay in or exit the progenitor zone to integrate neural or mesodermal tissues. Indeed, high Bra levels confer high motility that pushes cells to join the paraxial mesoderm, while high levels of Sox2 tend to inhibit cell movement forcing cells to integrate the neural tube. Mathematical modelling captures the importance of cell motility regulation in this process and further suggests that randomness in Sox2/Bra cell-to-cell distribution favors cell rearrangements and tissue shape conservation.

22/11/21 – Yoan Coudert (ENS, Lyon)

Symplasmic auxin movement and the evolution of plant architecture

The successful colonization of land by plants was accompanied by the diversification of their branching architecture. The phytohormone auxin is a major regulator of branch initiation and has a similar inhibitory role in flowering plants and mosses, two major land plant lineages that diverged from their most recent common ancestor several hundred million years ago. PIN-mediated polar auxin transport is crucial for auxin function in flowering plant branching control. Long-range tropic auxin gradients are sustained locally through the regulation of cell-to-cell connectivity at the level of plasmodesmata, although this is comparatively a minor pathway. In the moss Physcomitrella patens, an extant representative of early land plants, PIN proteins have a minor role in leafy shoot branching control and the symplasmic pathway could instead represent the main route for auxin movement in the stem. Using a combination of developmental genetics and computational modeling, we explore the role of symplasmic fields and plasmodesmal gating in auxin movement, and thereby assess their contribution to the evolution of plant morphogenesis.

06/12/21 – Marie Manceau

Developmental Control of Avian Skin Patterning

During pattern formation, morphogenetic events provide a response of the naïve tissue to chemical and mechanical positional cues. To what extent these processes shape pattern establishment and contribute to natural variation remains unclear. We studied cell dynamics occurring during the emergence of feather array geometries in birds, which involves a gradual regionalisation of the skin through self-organisation. We identified highly dynamic modifications of local cell density, movement, and shape occurring during primordia emergence in the Japanese quail. Using inter-species comparison in poultry, finch, emu, ostrich and penguin embryos, followed by perturbation of skin architecture ex vivo, we showed that oriented anisotropy of dermal cells prior to primordia formation is necessary for the regularity of the final array. Our results provide key insights into the cellular basis of self-organisation and demonstrate that initial tissue morphology constrains pattern attributes, uncovering a morphogenetic mechanism contributing to pattern evolution.

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Lent Term 2022

24/01/2022 – Marie-Cécile Caillaud (CNRS , Lyon)  

Characterization of a Mechanical Hotspot for Cell Plate Guidance Near an Adjacent Three-Way Junction 
 
When it comes to building an organ, cells need to coordinate with each other to form a functional tissue layer. In epithelia, cells attach to each other forming at their edges. In animals, mechanical stresses and mechano-sensitive signaling pathways play a central role in the formation and maintenance of three-way junctions (3WJ), which are topologically stable structures. In walled multicellular organisms, like land plants, the coordination of the 3WJ formation during cell division, and the corresponding avoidance of 4WJ, remains poorly understood and is often pictured as a passive consequence of cell division. Here, we report the existence of two positions at a conserved distance, above and below an existing 3WJ where cell plate insertion could occur in the Arabidopsis root cortex. This phenomenon, observed in other plants, is under genetic control: In an Arabidopsis mutant sac9-3, the cell plate abnormally attaches at two equidistant positions from an adjacent 3WJ, both in the root and shoot. The number of ill-formed junctions in sac9-3 mutant increased with the intensity of turgor-induced stresses borne by cell walls. This confirms our initial hint that stress plays a role in cell junction formation. Moreover, the sac9-3 mutants feature an impaired metabolism of the PI(4,5)P2 phospholipid suggesting that lipid within the plasma membrane could play a role in the mechano-transduction pathway guiding cell plate attachment. 

31/01/2022 Sundar Naganathan (EPFL, Lausanne) 

Emergence of a left-right symmetric body plan during embryonic development 

Vertebrates are characterized by a left-right symmetric muscle and skeletal system that emerges from bilateral somites during embryonic development. Left-right symmetry is vital for adult mechanical movements and a loss of symmetry is associated with debilitating skeletal disorders such as scoliosis. Symmetry is often assumed to be a default state in somite formation, however, it remains unknown how robust somite shapes and sizes at the same position along the body axis emerge on the left and right sides of the embryo. By imaging left-right somite formation in zebrafish embryos using light-sheet microscopy and by developing automated image analysis tools, we reveal that initial somite anteroposterior lengths and positions are imprecise and consequently many somite pairs form left-right asymmetrically in contrast to the textbook view. Strikingly, these imprecisions are not left unchecked and we find that lengths adjust within an hour after somite formation, thereby increasing morphological symmetry. We discover an error correction mechanism, where length adjustment is facilitated by somite surface tension, which we show by comparing in vivo experiments and in vitro single-somite explant cultures with a mechanical model. We propose that tissue surface tension provides a general mechanism to adjust shapes and ensure precision and symmetry of tissues in developing embryos. 

31/01/2022 Xuan Liang (PDN, Cambridge) 

CADHERIN mediated AMIS localisation – Using mouse embryonic stem cells 3D culture as a model 

Individual cells within de novo polarising tubes and cavities must integrate their forming apical domains into a centralised apical membrane initiation site (AMIS). This is necessary to enable organised lumen formation within multi-cellular tissue. Despite the well documented importance of cell division in localising the AMIS, we have found a division-independent mechanism of AMIS localisation that relies instead on CADHERIN-mediated cell-cell adhesion. Our study of de novo polarising mouse embryonic stem cells (mESCs) cultured in 3D suggest that cell-cell adhesion directs the localisation of apical proteins such as PAR-6 to a centralised AMIS. Unexpectedly, we also found that mESC cell clusters lacking functional E-CADHERIN were still able to form a lumen-like cavity in the absence of AMIS localisation and did so at a later stage of development via a ‘closure’ mechanism, instead of via hollowing. This work suggests that there are two, interrelated mechanisms of apical polarity localisation: cell adhesion and cell division. Alignment of these mechanisms in space allows for redundancy in the system and ensures the development of a coherent epithelial structure within a growing organ. 

07/02/2022 Alexander Nestor-Bergmann (PDN, Cambridge) 

Adhesion-regulated junction slippage controls cell intercalation dynamics in an Apposed-Cortex Adhesion Model

Cell intercalation is a key cell behaviour of morphogenesis and wound healing, where local cell neighbour exchanges can cause dramatic tissue deformations such as body axis extension.  While substantial experimental work has identified the key molecular players facilitating intercalation, there remains a lack of consensus and understanding of their physical roles. Existing biophysical models that represent cell-cell contacts with single edges cannot study neighbour exchange as a continuous process, where neighbouring cell cortices must uncouple. I will present an Apposed-Cortex Adhesion Model (ACAM) to understand active cell intercalation behaviours in the context of a 2D epithelial tissue. The junctional actomyosin cortex of every cell is modelled as a continuous viscoelastic rope-loop, explicitly representing cortices facing each other at bicellular junctions and the adhesion molecules that couple them. The model parameters relate directly to the physical properties of the key subcellular players that drive dynamics (actin, myosin and adhesion), providing a multi-scale understanding of cell behaviours. The ACAM predicts that active junctional contractility and cortical turnover are sufficient to shrink and remove a junction, while the growth of a new, orthogonal junction follows passively. The model reveals how the turnover of adhesion molecules specifies a friction that regulates tissue dynamics and tension transmission by controlling slippage between apposed cell cortices. Increasing the friction from adhesion in an actively intercalating tissue can lead to the formation of rosette structures, where vertices become common to many cells.

07/02/2002 Laura Pellegrini (LMB, Cambridge)

Breaking the barrier: CSF-producing choroid plexus organoids model pathogen and drug entry to the brain  

The choroid plexus (ChP) is a highly conserved and surprisingly understudied secretory tissue in the brain. This tissue displays a number of important functions in the brain such as forming a protective epithelial barrier and secreting the cerebrospinal fluid (CSF). The CSF is important for the maintenance of physiological levels of nutrients in the brain, for the transport of signalling molecules and growth factors and for its protective role in the regulation of intracranial pressure. To explore the role of the ChP-CSF system, we recently established a protocol to generate ChP organoids using a combination of signalling molecules that are physiologically present during the stages of development of this tissue. More interestingly, not only do these organoids develop the ChP but they also recapitulate fundamental functions of this tissue, namely secretion and formation of a tight epithelial barrier. Combining single-cell RNA-sequencing with immunohistochemical and EM validation, we detected the presence of ChP specific channels and transporters localised on the apical brush border of the ChP epithelium. By testing different compounds, we were able to demonstrate the selective permeability of the ChP barrier in vitro, using NMR. In addition, we noticed the formation of large fluid-filled cysts protruding from the organoids, the contents of which, analysed by mass spectrometry, highly resembles human CSF. Finally, we used this model to test pathogen entry in the brain and we infected the organoids with live SARS-CoV-2. We found that SARS-CoV-2 infects ChP epithelial cells causing damage of this key brain barrier. In conclusion, we believe this system represents an excellent tool to study pathogen and drug entry in the brain. 

14/02/2002 Alberto Elosegui-Artola (FCI, London) 

Understanding the role of the extracellular matrix: from elasticity to viscoelasticity 

The mechanical properties of the extracellular matrix (ECM) regulate cellular processes during development, cancer and wound healing. The vast majority of research efforts in this field have focused on the ECM’s elasticity as a leading determinant of cell and tissue behaviour. We have previously shown the biophysical mechanism which cells sense tissue elasticity and transduce it into downstream signaling and how force transmitted from the ECM to the nucleus is enough to translocate transcriptional regulators to the nucleus. However, the ECM is not merely elastic but is instead both viscous and elastic. Despite the universality of ECM’s viscoelasticity, how viscoelasticity affects tissue function is unknown. I will present our results where we show that the passive viscoelastic properties of the ECM can regulate multicellular tissues spatial and temporal organization both in breast spheroids and intestinal organoids. By combining computational modelling with experiments, we confirm that the viscoelastic properties of the matrix regulate spherical tissues symmetry breaking, invasion and branching. Furthermore, ECM viscoelasticity controls epithelial to mesenchymal transition and tumour growth both in vitro and in vivo. Altogether, our work demonstrates the role of viscoelasticity in symmetry breaking instabilities associated with fingering, a fundamental process in morphogenesis and oncogenesis, and suggest ways of controlling tissue form using the extracellular matrix. 

21/02/2022 – Adrienne Roeder (WICMB, Cornell)

Mechanisms generating robustness in plant organ size and shape 

Development is remarkably reproducible, producing organs with the same size, shape, and function repeatedly from individual to individual. Yet, these reproducible organs are composed of highly variable cells. My laboratory focuses on the mechanisms that produce cellular heterogeneity and organ size and shape robustness. We use a combination of genetics, live imaging, computational image processing, mechanical assays, and computational modeling to determine how robustness emerges from the dynamics of cell division, cell growth, mechanics, and gene expression. We use Arabidopsis sepals as a model system because sepals are relatively unresponsive to the environment, there are four sepals on each flower so robustness can be assessed easily, and sepals are accessible for imaging and manipulation. Surprisingly, we are finding that plants utilize stochasticity and heterogeneity to generate robustness in development. Today I will discuss our results on the variable organ size and shape 2 (vos2) mutant, which has allowed us to identify a specific role for TOR signaling and translation in robustness of sepal primordium initiation.  I will discuss live imaging of developing Arabidopsis leaves and look at how leaves form flat blades. Finally I will talk about how rotation of the asymmetric division plane of the moss apical stem cell generates a spiral pattern of leaves. 

28/02/2022 – Paul K. Strother (Boston College) 

The fossil origins of eukaryotic morphogenesis: exploring the beginnings of complex multicellularity in the Holozoa 

The fossil record is a (backwards) time machine that provides us with the occasional snapshot of former life on Earth. Phosphatic nodules from the Torridonian Sequence in in the NW Scottish Highlands preserve lake bottom sediments from 994 ± 48 Ma and some layers include 3-dimensionally preserved cells and cell clusters. The simple morphologies of unicellular organisms throughout much of the Precambrian record have permitted the recognition of only a handful of protist-level clades. The Torridonian, however, has preserved more complex morphology in the form of various cell clusters, some of which contain 2 clearly distinct cell types. A process of elimination, based on cell-cell morphology led us to propose the Ichthyosporea as the closest morphological analog to this new form, Bicellum Brasieri. Nick Butterfield pointed out years ago that individual Precambrian deposits might be conducive to the preservation of life-cycle varieties, and, indeed, we found several populations of what we infer to be the intermediate phases in the Bicellum life cycle. These include the initiation of multicellularity through the formation of a (multinucleate) syncytium, followed by cellularization into isodiametric cells forming a parenchymatous stereoblast. Some stereoblasts preserve an admixture of a small number of elongate cells within the largely isodiametric cell mass. Others show a single enclosing layer of elongate cells, that we infer to have migrated to the periphery of the cell mass. In the inferred mature, cyst, form, the elongated cells have thickened walls and they are devoid of cell contents. Even though the dynamics of this reconstruction are speculative, fossil themselves do provide the basis for an independent morphogenic model from which to explore the early evolution of morphogenesis eukaryotes. For example, Malcolm Steinberg’s Differential Adhesion Hypothesis (DAH) provides a possible causal mechanism for the movement of elongate cells to the cell mass periphery. Similar dynamics have been shown in both adhesion experiments with living cell masses and computer simulations. It is interesting to speculate that mechanistic aspects of development in early eukaryotes may have incorporated a combination of D’Arcy Thompsonian ‘physical forces’ (or Kauffman’s ‘order for free’) in conjunction with the chemical environmental signalling that eventually led to genetic control of cell development and differentiation in the evolving holozoan lineage. The extent to which such elements will become incorporated into new models of hypothetical protistan ancestors to the Metazoa remains to be seen, but Bicellum does demonstrate that simple cell-sorting in protists was taking place in lake bottoms almost a billion years ago. 

07/03/2022 – Natalie Dye (POL, Dresden) 

Getting into shape: new insights into morphological patterning from the Drosophila wing 

How cellular activity is coordinated over long spatial and temporal timescales to build complex 3D tissue morphologies during animal development remains a fascinating open question in biology. We study collective cellular behavior during epithelial morphogenesis using the Drosophila wing as a model. At the transition between larval and pupal stages, the developing wing tissue undergoes a complex 3D remodeling process called eversion, where deep tissue folds unfold and the dorsal and ventral surfaces find each other and appose. Using confocal and multi-angle light sheet microscopy, we have quantified the patterns of cell and tissue shape changes occurring during this process. Our data suggest that spatial patterns of cell morphology that emerge during the larval growth phase may prepone particular 3D tissue shape changes during the subsequent eversion stage. We are testing this idea using theoretical approaches and genetic perturbation. This work broadens our understanding of tissue morphogenesis by describing a novel interplay between cellular packing geometry and 3D tissue shape changes. 

14/03/2022 – Kristian Franze (PDN, University of Cambridge)

The chemo-mechanical regulation of brain development 

During brain morphogenesis, neurons are highly motile. However, even though motion is driven by forces, our current understanding of the physical interactions between neurons and their environment is very limited. We here show how local mechanical brain tissue properties contribute to guiding neuronal axons.  In vivo time-lapse atomic force microscopy revealed viscoelasticity gradients in developing brain tissue, which axons followed towards soft. Interfering with brain stiffness and mechanosensitive ion channels in vivo both led to aberrant neuronal growth patterns with reduced fasciculation and pathfinding errors. Moreover, mechanical signals not only directly impacted neuronal growth but also indirectly by regulating neuronal responses to and the availability of chemical guidance cues, strongly suggesting that chemical and mechanical signaling pathways are intimately linked, and that their interaction is crucial for morphogenetic events. 

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Michaelmas Term 2022

25/04/2022 – Matteo Rauzi (University Côte d’Azur, Nice) 

Composite morphogenesis: how can a tissue fold and extend at the same time 

During embryo development, epithelia can undergo different shape transformations. While these changes can be sequential, and thus driven by specific sequential cellular mechanisms, this is not always the case. A single tissue can undergo multiple simultaneous shape transformations resulting in a composite process. For instance, in vertebrates, during neurulation, the dorsal tissue folds forming the neural tube while elongating along the anterior-posterior axis separating the future head from the anus (Keller, 2002). This raises an important question: how can a tissue undergo multiple simultaneous shape transformations if each transformation is per se driven by different and functionally specific cellular mechanisms? In addition, which signaling pathways are controlling composite morphogenetic processes? We use the early gastrulating Drosophila embryo as model system and focus on the process of mesoderm invagination during which the tissue on the ventral side of the embryo simultaneously folds and extends. By using advanced multi-view light sheet microscopy coupled to infrared femtosecond laser manipulation, optogenetics and quantitative big data analysis, we shed new light on the genetic synergy, the mechanisms and mechanics controlling and driving composite morphogenesis. 

09/05/22 – Daniel Kierzkowski (Montreal University) 

Cell-type-specific behaviour underlies cellular growth variability in plants

In plants, cell growth is controlled by positional information, yet the behavior of individual cells in an expanding tissue is often highly heterogeneous. The origin of this variability is still unclear. Using quantitative time-lapse imaging we determined the source and relevance of cellular growth variability in developing organs of Arabidopsis thaliana.  We showed that cell-autonomous behavior of specialized cells is the main source of local growth variability in otherwise homogeneously growing tissue. Growth differences are buffered by the immediate neighbors of specialized cells to achieve robust organ development. 

16/05/2022 – Takashi Hiiragi (EMBL, Heidelberg)

Multicellular coordination in context

A defining feature of living systems is the capacity to break symmetry and generate well-defined forms and patterns through self-organisation. Our group aims to understand the design principle of multicellular living systems using early mouse embryos as a model system. We developed an experimental framework that integrates biology, physics and mathematics, to understand how molecular, cellular and physical signals are dynamically coupled across the scales for self-organisation.

23/05/2022 – Aissam Ikmi (EMBL, Heidelberg) 

Drivers of cnidarian morphogenesis  

Morphogenesis is a highly dynamical process in which contractility and motility behaviors emerge at different levels, from cellular to tissue, and organismal. However, little is known about how organism-scale behaviors impact morphogenesis. Here, we use the cnidarian Nematostella vectensis as a developmental model to uncover a mechanistic link between organism size, shape and behavior. Using quantitative live imaging in a large population of developing animals, including extensive behavioral profiling, combined with molecular and biophysical experiments, we demonstrate that the muscular hydraulic machinery that controls body movement drives larva-polyp morphogenesis. In addition, I will discuss a fascinating feature of cnidarian biology. For humans, our genetic code determines that we will grow two arms and two legs. The same fate is true for all mammals. Similarly, the number of fins of a fish or legs and wings of an insect is embedded in their genetic code. I will describe how sea anemones defy this rule. 

30/05/2022 – Geraldine Jowett (Gurdon Institute, Cambridge) 

Organoids – how can they shed light on immune-mediated development and disease? 

Model organisms and in vitro mammalian models have developed hand in hand over the past century to offer ever more complex toolboxes to study how creatures are created. In this talk, the growing prevalence of 3D mammalian organoid systems will be discussed, focussing on a balance between their limitations and their potential.  As an example, their ability to shed light on bi-directional interactions between different tissue types such as epithelial and innate immune cells will be discussed in the context of development and disease. 

30/05/2022 –  Antonia Weberling (PDN, Cambridge) 

Differentiation of the extra-embryonic endoderm is required for development of the pluripotent epiblast 
Implantation of the mouse blastocyst initiates a sequence of remodelling and differentiation events that lead to the formation of the post-implantation egg cylinder. During this process, the primitive endoderm differentiates into the visceral endoderm. To elucidate extraembryonic endoderm lineage progression in peri-implantation embryos, we generated a single-cell sequencing dataset of E5.0 embryos. Our analysis shows that primitive to visceral endoderm transition includes an intermediate state which exhibits distinct signalling activities, including upregulation of Bmp signalling and transient downregulation of basement membrane component Lama1. Assessment of Hnf1b-/- embryos, which degenerate upon implantation, reveals a previously unknown interaction between epiblast and visceral endoderm required for epiblast post-implantation survival. Single-cell profiling of the Hnf1b-/- E5.0 visceral endoderm demonstrates developmental delay, misexpression of the pluripotency marker Pou5f1 and consistent loss of nutrient transport pathways. These results suggest that upregulation of nutrient transport pathways during the primitive to visceral endoderm differentiation is essential for successful post-implantation development. 

13/06/2022 – Giovanni Dalmasso (EMBL Barcelona, Sharpe Lab) 

4D reconstruction of developmental trajectories 

The continuous progress in imaging and computer modelling have increased our understanding of morphogenetic processes at different scales, from organs up to entire organisms. However, in the case of complex animal models (e.g., mouse embryogenesis), is not yet entirely possible to observe in real time the full growth of a developing embryo. Consequently, the current 3D data availability in these cases, even if extensive and detailed, provides only a characterisation of development at discrete moments in time, through single snapshots. To fill this gap, we set up a computer-based approach to describe the evolution in space and time of developmental stages from 3D volumetric images. Specifically, we represent each data into the spherical harmonics space, and we reconstruct the volumes using the values of the spherical harmonics’ coefficients interpolated in time (over the developmental stages). As a result, the reconstruction describes a continuous and smooth changing shape over space and time. We tested this approach using two different data sets: (1) mouse limb buds and (2) mouse hearts. (1) ~100 optical projection tomography (OPT) of mouse limbs were used and the result represents the 4D growth of an ideal limb which considers the common characteristics and features of all the limbs in the data set. We are recreating the growing process starting from E10 (i.e., 10 days after conception) when the limb bud is just a small bump of tissue and finishing at E12.5 when the limb bud already shows a distinctive “paddle” shape. This approach proved to be robust even in the case of mouse hearts (2) where only a limited number of sample (~30) were used. Also, in this case we were able to create a continuous time-course describing the heart development of a mouse starting from 10 to 29 somites. This approach, able to combine the complexity of different arbitrary shapes over space and time, not only provides a quantitative basis for validating predictive models, but it also increases our understanding of morphogenetic processes from a purely geometrical point of view. 

13/06/2022 – Aleksandra Marconi (Zoology Department, Santon lab) 

Exploring variation in neural crest development among East African cichlid fishes 

The cichlid fishes comprise the largest extant vertebrate family and are the quintessential example of rapid “explosive” adaptive radiations and phenotypic diversifications. Despite the relative genomic homogeneity, cichlids harbour a spectacular intra- and interspecific diversity in morphology, behaviour, and ecological specialisation. Akin to other vertebrates, a considerable proportion of cichlid phenotypic diversity involves structures derived from a common progenitor cell population – the neural crest (NC). These include distinctive pigmentation patterns and a vast variation in craniofacial morphologies. To investigate the role of NC in morphological evolution of East African cichlids, we compared the embryonic and NC development between three phenotypically divergent cichlid species (Astatotilapia calliptera, Rhamphochromis sp. ‘chilingali’ and Tropheops sp. ‘mauve’) endemic to Lake Malawi and its basin. Our results revealed interspecific variability in many features of embryogenesis that could potentially influence the concomitant formation of the NC and its derivatives. By investigating the migratory behaviour of NC cells across their ontogeny, we identified striking temporal and spatial variation. To further explore the differences in morphogenesis of the NC, we are combining novel 3D morphometrics approaches with transcriptomic and regulatory analyses at most divergent stages of NC development between the study species. 

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