Grant: Operating Grant

At birth, a baby is composed of billions of cells organized in functional organs and tissues. To achieve this, the developing embryo has to multiply its cells but, more importantly, has to specify over 200 new cell types from "naive" cells and organize them in space such that they interact with the right environment and ultimately develop into a functional organs. A failure in this process can lead to developmental defects ranging from chronic diseases to embryonic death. We are studying the basic biological mechanisms of cell type specification and spatial organization. For this we use the mouse renal system that is relatively simple in its cellular composition and amenable to sophisticated developmental studies. We have previously identified the "master regulators" Pax2 and Pax8 that are both required and sufficient to induce the renal lineage. We built on this finding to identify the molecular network regulated by Pax2/8 and identified Gata3 as an important mediator of Pax2/8 function. Among other things Gata3 regulates the elongation of the renal primordium to form the embryonic kidney. In this proposal, we want to understand which signals from surrounding tissues activate Pax2/8 to specify provide the renal identity "naive" cells. We also propose to identify and characterize the biological forces driving the renal primordium to elongate in the embryo tail to connect to the bladder and form the kidney. A failure in renal promordium formation or elongation leads to a complete absence of kidneys and embryonic death. Importantly, partial failures in this process lead to a disease group called Congenital Anomalies of the Kidney and Urinary Tract (CAKUT). CAKUT affects as many as 1:100 newborn and is the most important cause of chronic kidney diseases and renal transplant in children. By elucidating the mechanisms of renal primordium specification and elongation we will help understand and better manage the treatment of children affected with CAKUT.