Biology subjects

Siggia, E.

Publications and source records attributed to Siggia, E..

6 recordsLinked to original sources

bioRxiv2023

A geometrical model of cell fate specification in the mouse blastocyst

The lineage decision that generates the epiblast and primitive endoderm from the inner cell mass (ICM) is a paradigm for cell fate specification. Recent mathematics has formalized Waddingtons landscape metaphor and proven that lineage decisions in detailed gene network models must conform to a small list of low dimensional stereotypic changes called bifurcations. The most plausible bifurcation for the ICM is the so-called heteroclinic flip that we define and elaborate here. Our reanalysis of recent data suggests that there is sufficient cell movement in the ICM so the FGF signal, which drives the lineage decision, can be treated as spatially uniform. We thus extend the bifurcation model for a single cell to the entire ICM by means of a self-consistently defined time-dependent FGF signal. This model is consistent with available data and we propose additional dynamic experiments to test it further. This demonstrates that simplified, quantitative, and intuitively transparent descriptions are possible when attention is shifted from specific genes to lineages. The flip bifurcation is a very plausible model for any situation where the embryo needs control over the relative proportions of two fates by a morphogen feedback.

developmental biology↗

bioRxiv2023

Clonal neural tube organoids self-organise floorplate through BMP-mediated cluster competition

The neural tube (NT) has been a hallmark example of embryonic induction and patterning whereby the notochord induces an organiser, the floorplate, that secretes Sonic Hedgehog (SHH) to pattern the surrounding field of neural progenitors. On the other hand, NT organoids (NTOs) formed from embryonic stem cells (ESCs) undergo spontaneous floorplate formation and patterning in the absence of their normal embryonic inducers. Understanding how stem cells undergo regulative organiser formation is a central challenge in biology. Here, we investigated the self-organisation of a SHH-expressing floorplate organiser using clonal NTOs. Expression of FOXA2, a floorplate transcription factor, was initially spatially scattered before resolving into multiple clusters. These FOXA2+ clusters underwent competition and physical sorting, resulting in a stable "winning" floorplate. We identified BMP signalling as a key governor of long-range cluster competition. FOXA2+ clusters expressed BMP4 ligand suppressing FOXA2 in receiving cells, while simultaneously expressing the BMP-inhibitor NOGGIN to secure FOXA2+ cluster survival. Genetic mutation of Noggin perturbed the floorplate not only in NTOs but also in vivo at the mid-hindbrain region of the mouse NT. These results demonstrate how the floorplate can form autonomously without its well-known inducer, the notochord, suggesting redundant mechanisms ensuring robustness. Defining molecular pathways that govern organiser self-organisation is critical in harnessing the developmental plasticity of stem cells toward directed tissue engineering.

developmental biology↗

bioRxiv2021

Self-organized morphogenesis of a human neural tube in vitro by geometric constraints

Understanding how human embryos develop their shape is a fundamental question in physics of life with strong medical implications. However, it is challenging to study the dynamics of organ formation in humans. Animals differ from humans in key aspects, and in particular in the development of the nervous system. Conventional organoids are quantitatively unreproducible and exhibit highly variable morphology. Here we present a morphologically reproducible and scalable approach for studying human organogenesis in a dish, which is compatible with live imaging. We achieve this by precisely controlling cell fate pattern formation in 2D stem cell sheets, while allowing for self-organization of tissue shape in 3D. Upon triggering neural pattern formation, the initially flat stem cell sheet undergoes folding morphogenesis and self-organizes into a millimeter long anatomically accurate model of the neural tube, covered by epidermis. We find that neural and epidermal human tissues are necessary and sufficient for folding morphogenesis in the absence of mesoderm activity. Furthermore, we find that molecular inhibition of tissue contractility leads to defects similar to neural tube closure defects, consistent with in vivo studies. Finally, we discover that neural tube shape, including the number and location of hinge points, depends on neural tissue size. This suggests that neural tube morphology along the anterior posterior axis depends on neural plate geometry in addition to molecular gradients. Our approach provides a new path to study human organ morphogenesis in health and disease.

developmental biology↗

bioRxiv2021

A landscape model for cell fate decisions during mesoendoderm differentiation in C. elegans based on Wnt dynamics

Geometric models allow us to quantify topography of the Waddington landscape and gain quantitative insights of gene interaction in cell fate differentiation. Often mutant phenotypes show partial penetrance and there is a dearth of quantitative models that can exploit this data and make predictions about new allelic combinations with no additional parameters. C. elegans with its invariant cell lineages has been a key model system for discovering the genes controlling development. Here we focus on the differentiation of the endoderm founder cell named E from its mother, the EMS cell. Mutants that convert E to its sister MS fate have figured prominently in deciphering the Wnt pathway in worm. We construct a bi-valued Waddington landscape model that predicts the effect on POP-1/TCF and SYS-1/beta-catenin levels based on the penetrance of mutant alleles and RNAi, and relates the levels to fate choice decisions. A subset of the available data is used to fit the model and remaining data is then correctly predicted. Simple kinetic arguments show that contrary to current belief the ratio of these two proteins alone is not indicative of fate outcomes. Furthermore, double mutants within a background reduction of POP-1 levels are predicted with no adjustable parameters and their relative penetrance can differ from the same mutants with the wild-type POP-1 level, which calls for further experimental investigations. Our model refines the content of existing gene networks and invites extensions to other manifestations of the Wnt pathway in worm.

developmental biology↗

bioRxiv2019

Mapping cell migrations and fates from a gastruloid model to the human primitive streak

Although fate maps of early gastrula embryos exist for nearly all model organisms, a fate map of the gastrulating human embryo remains elusive. Here we use human gastruloids to piece together part of a rudimentary fate map of the human primitive streak (PS). This is possible because stimulation with differing levels of BMP, WNT, and NODAL leads to self-organization of gastruloids into large and homogenous different subpopulations of endoderm and mesoderm, and comparative parallel analysis of these gastruloids, together with the fate map of the mouse embryo, allows the organization of these subpopulations along an anterior-posterior axis. We also developed a novel cell tracking technique that allowed the detection of robust fate-dependent cell migrations in our gastruloids comparable to those found in the mouse embryo. Taken together, our gastruloid derived fate map and recording of cell migrations provides a first coarse view of the embryonic human PS.

developmental biology↗

bioRxiv2017

Self-organization of a functional human organizer by combined WNT and NODAL signalling

In amniotes, the development of the primitive streak (PS) and its accompanying \"organizer\" define the first stages of gastrulation. Despite detailed characterization in model organisms, the analogous human structures remain a mystery. We have previously shown that when stimulated with BMP4, micropatterned colonies of human embryonic stem cells (hESCs) self-organize to generate early embryonic germ layers1. Here we show that in the same type of colonies WNT signalling is sufficient to induce a PS, and WNT with ACTIVIN is sufficient to induce an organizer, as characterized by embryo-like sharp boundary formation, epithelial-to-mesenchymal transition (EMT) markers, and expression of the organizer specific transcription factor GSC. Moreover, when grafted into chick embryos, WNT and ACTIVIN treated human cells induce and contribute autonomously to a secondary axis while inducing neural fate in the host. This fulfills the most stringent functional criteria for an organizer, and its discovery represents a major milestone in human embryology.

developmental biology↗