Grants and Contributions:

Grant or Award spanning more than one fiscal year. (2017-2018 to 2022-2023)

The long-term objective of this research program is to understand the biophysical mechanisms by which tissues take shape during embryonic development. Beyond cell proliferation and migration, organ morphogenesis indeed results from biomechanical forces exerted on cells and tissues. This relatively new dimension of developmental biology is still largely unexplored, especially in vertebrates. To address these questions, we focus on ureter maturation, a system that we have largely contributed to describe. During development, the ureter initially grows out of a previously established duct and must therefore be relocated to the bladder wall prior to urine production. We have shown that this process requires the elimination of the duct separating the ureter and the bladder by programmed cell death (apoptosis). We further identified important regulators of this process that either slow down or accelerate ureter maturation by affecting cell sensitivity to apoptosis.

Our short-term objective is to understand how apoptosis can generate a pulling force bringing together the ureter and the bladder . It is based on the surprising observation that the epithelial cells of the duct engulf dying cells such that the duct is “self-eliminating”. We hypothesize that this regulated elimination of dying cells creates a pulling force by gradual filling of the “void” created by cell death and phagocytosis. In support of this, we found that the rate of apoptosis correlates with the speed of duct elimination. We further observed that apoptotic cell shrinkage and engulfment by epithelial phagocytes are present and necessary for ureter displacement. Force generation by apoptosis is poorly explored in vertebrates and the idea of force generation by epithelial cell phagocytosis is an entirely new concept.

These findings raise two outstanding questions: Aim 1 - How is apoptotic cell elimination able to generate a pulling force bringing the ureter in contact with the bladder? Aim2 - How is the force of cell elimination, which occurs in all 3 dimensions, able to pull the ureter in a unidirectional manner? This force transfer and propagation implies the presence of counter forces allowing tissue movement in a single direction.

This work is important as it addresses an aspect of developmental biology that has been underexplored over the years, namely, the biophysical forces driving tissue organization during development. So far, these questions have focused largely on the role of cellular contractility (actomyosin). Here we put forward the innovative idea that biomecanical force generation can be driven by cell volume decrease and engulfment of apoptotic cells. For this, we bridge the fields of developmental biology and cellular biophysics. This work will bring a new understanding of the laws driving embryo development and will provide a unique environment to train the next generation of cell and developmental biologists.