The Kidney Foundation of Canada

Dr Maxime Bouchard 

Dr. Maxime Bouchard

McGill University, QC

Collective cell migration in urinary tract morphogenesis and disease

Co-applicant(s): Oraly Sanchez-Ferras

2018-2020:  $100,000 |  Biomedical Research Grants  |  Category: Kidney development

Lay Summary

Our laboratory works on the identification of genes affected in patients with “Congenital Anomalies of the Kidney and Urinary Tract” or CAKUT. This disease group is not well defined and includes patients with only one kidney, smaller kidneys, obstruction of the ureter or ureteral reflux. CAKUT affects 1 in 100 newborns and is the most frequent cause of chronic kidney disease and renal transplant in children.

The way we address the problematic of CAKUT is to try to reproduce the kidney and ureter defects in mice. Over the years we have generated and published about 10 different mouse strains with CAKUT-like urinary tract defects.

Most of the genes affecting kidney and ureter development act at a very early stage of urogenital system formation. They typically affect the formation of the primitive kidney (mesonephros) or the early stages of adult kidney development.

In this proposal, we used advanced molecular techniques (single cell RNA sequencing) to identify potential regulators of mesonephros development. We used the CRISPR approach to identify which candidates affected mesonephros development in the mouse embryo. This work identified a gene called Ymo1 that is involved in the formation modification of the cell skeleton. Changes in the structure of the cell skeleton (cytoskeleton) is responsible for the changes in cell shape that are necessary for cells to move (by themselves or in group) or become stiff and packed together.

We therefore propose to study our new mouse model to understand how the cell skeleton regulates the formation of the mesonephros but also the adult kidney and ureter. The genes – important for early kidney development are often also involved at later stages of kidney formation, which can generate other forms of CAKUT-like defects.
To fully understand the implication of our new regulator of kidney development in CAKUT, we also propose to sequence the DNA of 95 patients (children) with CAKUT and determine if they carry mutations in this gene.

This work will be beneficial to public health and is relevant to the KFOC mission in several ways. It will document the importance of the cell cytoskeleton in kidney development (for which we know little); it will generate murine models to better understand how defects in kidney development lead to CAKUT; it will help better define the disease group CAKUT for which there is no clear molecular definition at this time; and finally, it will help pediatric nephrologists decide on the best diagnostic and method of intervention when they are referred patients affected with kidney and ureter malformations at birth.