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.

90 年代初在诺丁汉大学获得生物学学位后，我在华威大学跟随 Hugh Woodland 教授攻读博士学位，重点研究青蛙内胚层形成（Hudson 等，  1997）。当我寻找实验室进行博士后研究时，我犹豫不决是继续使用非洲爪蟾还是转向其他系统。我的命运是在马赛 IBDM 与帕特里克·勒梅尔 (Patrick Lemaire) 进行博士后采访时决定的，当时我发现了他对海鞘胚胎的热情，尽管当时他的实验室仍然只研究非洲爪蟾。我接受了帮助他在实验室建立海鞘模型的挑战，但事后看来，我有点天真，没有意识到这将是一个多么大的挑战！在此期间，我们有幸还得到了经验丰富的海鞘胚胎学家 Hitoyoshi Yasuo 和 Sébastien Darras 的帮助。作为一名发育生物学家，海鞘胚胎最吸引我的是不变的细胞分裂模式和谱系，这非常有用，因为它允许人们识别和命名每个胚胎中的相同细胞，从而了解胚胎的起源和最终结果。细胞在每次发育转变过程中的命运。在那个前基因组时代，我开始使用简并 PCR 寻找脊椎动物调控基因的同源物。当我分离出几个在神经组织中表达的基因（Otx和Gsx）时，突破出现了，我的海鞘冒险的下一步开始了。在 Patrick 的实验室中，我主要关注外胚层细胞中的神经诱导（“大脑”诱导）和 FGF-ERK 信号通路的作用，这些工​​作有助于对这一过程进行更多的分子理解（Hudson & Lemaire，2001  ）。2003年，我成为法国国家科学研究中心（CNRS）的一名研究员，加入了滨海自由城生物学发展实验室（LBDV）人吉康夫（“Yas”）领导的“细胞命运”团队。 ）。

我的研究深受 Ian Meinertzhagen 博士实验室的精彩描述的启发，这些描述显示了发育中的神经板的规则网格状组织和神经板细胞分裂的有序模式（Nicol & Meinertzhagen，1988  ）。这些神经板图谱帮助我们表明，每个神经板细胞都具有独特的基因表达谱（Esposito et al.,  2016；Hudson et al.,  2007；Hudson & Lemaire,  2001；Hudson & Yasuo,  2005）。然后，我们可以展示神经板如何通过 Nodal 和 Delta/Notch 信号在内侧-横向轴上形成图案，以及如何通过差异 ERK 活动沿着前后轴形成图案（Esposito 等人，2016；  Haupaix等人，  2014；Hudson等人，  2007 年；Hudson 和 Yasuo，  2005 年；图 1a)。值得注意的是，在每个神经谱系中，每个前体细胞都会接受独特的信号通路组合，从而促进其独特的转录状态（图1a）。

最近，我们与计算化学家合作，组建了“ERKtivation”团队（图 2），在一个项目中解决细胞如何解释噪声或分级信号以做出决定性细胞命运决定的基本问题。该项目重点关注 32 细胞阶段外胚层细胞神经诱导的第一步。我们采用定量和计算方法来尝试了解在此过程中，在前外胚层的八个细胞中，一对神经前体细胞是如何在每个胚胎的相同位置指定的（图1b中的粉红色细胞；Bettoni等人） .,  2023 ; Williaume 等人,  2021 )。我们发现，在每个外胚层细胞中，ERK 激活水平与细胞与表达 FGF 的中内胚层细胞和表达肝配蛋白的外胚层细胞接触的面积相关（如图 1b 中的 FGF 所示）。这种相当渐进的 ERK 激活反应被转化为立即早期基因Otx的陡峭转录反应，因此其表达仅限于神经前体细胞。肝配蛋白的“抑制”作用对于将 ERK 水平保持在非神经外胚层中Otx诱导阈值以下至关重要。我们现在正试图从机制上理解Otx转录开关对 ERK 的类似反应是如何产生的。我们希望继续采用这种协作方式，迄今为止，这种方式既非常具有挑战性，又是一次非常令人兴奋和有益的经历，在许多困惑、潦草的解释和良好的幽默感的帮助下。