A 2026 Crick PhD project with Rashmi Priya.
Project background and description
The overarching goal of our lab is to understand how functional organs are built during embryonic development using a well-suited model system – the developing zebrafish heart. The heart is the first organ to form and function during embryonic development [1-4]. To supplement the increasing physiological demands of the growing embryos, the myocardial tissue develops numerous specialized structures for maximum efficiency. One such critical step in vertebrate cardiac development is trabeculation, which is crucial for heart function [1-4]. During trabeculation, the myocardial wall transforms from a single-layered epithelium into a complex 3D architecture consisting of two distinct cell types: an outer compact layer enveloping an inner contractile trabecular meshwork [2, 4]. Trabeculation defects cause cardiomyopathies and embryonic lethality [2, 4]. Yet, how the simple myocardial epithelium acquires intricate morphological complexity and diverse cell fates during heart development is not well understood.
Our work has made extensive progress towards understanding trabecular morphogenesis [1-4]. We have shown that differences in the mechanical properties of cells are sufficient to seed trabecular cells [2]. Cells with higher cytoskeletal tension delaminate from the outer layer to seed the inner trabecular layer and this spatial segregation is sufficient to induce differential cell fate program [2]. Notably, this delamination is spatially constrained in the outer curvature of the heart by mechanical fracturing of the underlying extracellular matrix (ECM) [5]. Eventually, these single trabecular cells recruit outer compact layer cells to mature into complex multicellular trabecular ridges, which span the ventricular lumen [4]. While the ridges mature, the remaining compact layer cells get softer and stretch, which triggers a sharp transition in the tissue area, activating rapid heart growth that expands blood filling capacity [4].
Building upon these findings and taking a systems biology approach, we want to understand how a functional beating heart is built during embryonic development. Zebrafish embryos offer several distinct advantages to study heart development. The embryos are easily accessible, amenable to extensive genetic manipulations and are transparent, thus enabling us to visualize a beating heart at single-cell resolution [2, 4]. Importantly, during the first week of development, zebrafish embryos can survive without a functional heart. This is a unique advantage, as it enables us to use experimental manoeuvres ablating heart functions, which is otherwise impossible to achieve in other model systems because of early lethality. Combining the excellent tractability of zebrafish embryos with quantitative imaging, transcriptomics, biophysics, genetics, and predictive theoretical modelling, we aim to address:
1. Feedback between mechanics, cell fate dynamics, and geometry driving tissue patterning.
2. How 3D topological meshworks are shaped, constrained, and canalized.
3. How nuclear integrity is sustained in a developing beating heart.
4. Morphogenesis and Mechanics of organ scaling and regeneration.
5. Bioelectricity of Morphogenesis.
Candidate background
The suitable candidate will address one of these fundamental questions by using cross-disciplinary approaches from cell biology, genetics and theoretical physics, using 4-D live imaging, quantitative image analysis, optogenetics, biophysical manipulations, live biosensors, knock-in technology and controlled genetic perturbations. The specific details and aims of the project will be developed in consultation with the supervisor and will be driven by the candidate’s interest and training.
I am particularly interested in receiving applications from candidates with a background in cell and developmental biology and a strong interest in pursuing interdisciplinary collaborative research. Prior expertise in microscopy, quantitative image analysis, molecular biology, computational tools and embryological techniques is desired.
