Polarity, patterning and fate specification during embryonic development

A 2025 Crick PhD project with Nate Goehring.

Arguably, the central challenge in developmental biology is to understand how the enormous diversity of cell form, fate, and function that is typical of multicellular organisms arises from a single fertilized egg. To address this challenge, we use the early embryo of the nematode C. elegans as a model as it provides a rich and highly tractable experimental playground for defining core principles in cell and developmental biology.

One common feature of embryonic development that is linked to specification of cell fate is asymmetric cell division – the process by which a single mother cell gives rise to daughter cells with distinct identities. Asymmetric divisions are common in stem cell-like lineages and turn out to be a defining feature of the early development of C. elegans.

Beginning with the division of the fertilized egg (zygote), a series of asymmetric divisions specify the major developmental lineages that make up the adult tissues. During each of these cell divisions, the cell must first convert specific spatiotemporal cues into stable molecular asymmetries, a process referred to as cell polarization. The polarized cell must then ensure fate specifying molecules are differentially inherited by the two daughter cells where they can induce distinct developmental programmes.

Much of the work in the lab focusses on this process of cell polarization as specified by a set of proteins known as the PAR-titioning defective or PAR proteins. During asymmetric division, PAR proteins self-organise into opposing membrane-associated domains, which then serve as the key spatial regulators that direct division asymmetry.

Projects in the lab generally centre around (but are not limited to) two core themes:

1. Elucidating design principles underlying self-organization of PAR proteins into patterns – What are the relevant network feedback circuits, how do they emerge from underlying molecular behaviours (oligomerization, kinase-substrate interactions, membrane association), and how do they drive the emergence of stable patterns? [e.g. 1-2]
2. Integrating polarity into developmental programmes – How does the polarity network integrate information from developmental cues? How do considerations of time (cell cycle, developmental stage) and space (cell size/shape) impact polarity? How is polarity “read out” robustly by downstream processes to allow cells to make robust decisions? [e.g. 3-5]

To address these questions, we take an interdisciplinary approach that spans disciplines and scales of analysis, often moving between in vivo, in vitro and computational studies. This approach is aided by the reproducibility of early C. elegans development and as well as its amenability to quantitative perturbation and imaging techniques. This approach lets us link processes occurring at various scales from molecule to system and thereby identify core design principles of how these networks operate.

Note that this project description illustrates the types of questions that occupy us in the lab. Projects will be developed together with the supervisor, taking into account the student’s background and scientific interests.

Candidate background

We are looking for a motivated student to tackle these fundamental questions within a multidisciplinary environment. There is substantial freedom to tailor the research project to the interests and aptitude of the student. This project potentially involves a broad range of techniques including confocal/light-sheet/TIRF/super-resolution microscopy, quantitative image analysis, single particle tracking, optogenetics, RNAi, CRISPR, biochemistry, quantitative proteomics, chemical biology, and/or computational modelling. Hence, a variety of backgrounds will be considered (e.g. physics, biology, biochemistry). Passion for curiosity-driven research and willingness to embrace an interdisciplinary team effort will be essential. We consider the PhD as primarily an opportunity for students to develop into confident, independent scientists and thus students will be expected to show leadership in developing and managing their research projects.