Signals, grids, and geometry: In pursuit of understanding cell fate switches

Abstract

After a degree in Biology at the University of Nottingham in the early 90s, I studied for a PhD focusing on frog endoderm formation with Prof. Hugh Woodland at the University of Warwick (Hudson et al., 1997). When I was looking for a lab to do postdoctoral studies, I was undecided whether to continue with Xenopus or switch to a different system. My fate was sealed at a postdoc interview with Patrick Lemaire at the IBDM in Marseille when I caught his enthusiasm for ascidian embryos, although at that time his lab was still working only with Xenopus. I accepted the challenge to help him establish ascidians as a model in the lab, but with hindsight I was a little naive, not realizing how much of a challenge it was going to be! During this period, we were fortunate to also have help from experienced ascidian embryologists Hitoyoshi Yasuo and Sébastien Darras. What attracted me most about ascidian embryos, as a developmental biologist, was the invariant cell division pattern and lineage, which is extremely useful, as it allows one to identify and name the same cell in every embryo and thus to know the embryonic origin and eventual fate of cells as they progress through each developmental transition. In that pre-genomic era, I started off looking for homologues of vertebrate regulatory genes using degenerate PCR. A breakthrough came when I isolated a couple of genes expressed in neural tissue (Otx and Gsx) and the next step of my adventure with ascidians began. In Patrick's lab, I focused mainly on neural induction in ectoderm cells (“brain” induction) and the role of the FGF-ERK signaling pathway, work which contributed to a more molecular understanding of this process (Hudson & Lemaire, 2001). In 2003, I became a staff scientist of the Centre National de Recherche Scientifique (CNRS), joining the “Cell Fate” team led by Hitoyoshi Yasuo (“Yas”) in the Laboratoire de Biologie du Développement de Villefranche-sur-mer (LBDV).

My studies were greatly inspired by beautiful descriptions from the laboratory of Dr. Ian Meinertzhagen, showing the regular grid-like organization of the developing neural plate and the ordered pattern of neural plate cell divisions (Nicol & Meinertzhagen, 1988). These neural plate maps helped us show that each neural plate cell is characterized by a unique gene expression profile (Esposito et al., 2016; Hudson et al., 2007; Hudson & Lemaire, 2001; Hudson & Yasuo, 2005). We could then show how the neural plate is patterned across the medial-lateral axis by Nodal and Delta/Notch signals and along the anterior–posterior axis by differential ERK activity (Esposito et al., 2016; Haupaix et al., 2014; Hudson et al., 2007; Hudson & Yasuo, 2005; Figure 1a). Remarkably, within each neural lineage, each precursor receives a unique combination of signaling pathways, promoting its unique transcriptional state (Figure 1a).

More recently, we have teamed up with computational chemists, forming the “ERKtivation” team (Figure 2), in a project addressing a fundamental problem of how cells can interpret noisy or graded signals to make decisive cell fate decisions. The project focuses on the very first step of neural induction in ectoderm cells at the 32-cell stage. We have adopted quantitative and computational approaches to try to understand how, during this process, among the eight cells of the anterior ectoderm, one pair of neural precursors is specified in the same position in every embryo (pink cells in Figure 1b; Bettoni et al., 2023; Williaume et al., 2021). We found that, in each ectoderm cell, ERK activation levels correlate with the area of the cell in contact with both FGF-expressing mesendoderm cells and ephrin-expressing ectoderm cells (shown for FGF in Figure 1b). This rather gradual ERK activation response is converted into a steep transcriptional response of the immediate-early gene, Otx, so that its expression is restricted to neural precursors. A “dampening” effect by ephrin is critical to keep ERK levels below the threshold for Otx induction in non-neural ectoderm. We are now trying to understand mechanistically how the Otx transcriptional switch-like response to ERK is generated. We hope to continue with this collaborative approach, which has so far been both very challenging and a very exciting and rewarding experience, helped along by many states of bewilderment, scribbled explanations, and good humor.