Nephron progenitor cell regulation by SNF5
2The Alexander Silberman Institute of Life Science, The Hebrew University of Jerusalem
SNF5 is one of the core subunits of the SWI/SNF chromatin remodeling complex. It has been shown that loss of function (LOF) mutation in SNF5 is in many cases the solitary genetic aberration in kidney and brain malignant Rhabdoid tumor. Several mouse models were developed for brain Rhabdoid tumor. However, there are currently no animal models for kidney Rhabdoid tumor. Thus, we aimed to establish such model and to use it in order to study the cell origin of the tumor and the cellular and molecular mechanisms underlying its development. To accomplish this, we used the Cre-Lox system to induce LOF mutation specifically in the nephron progenitor cells (NPCs) and the nephrons derived from them. Notably, while the SNF5 LOF pups were born at the expected Mendelian ratio, they died several hours after birth. This early lethality was caused due to malformation of the kidneys. Specifically, we found that the transgenic kidneys hardly contain any nephrons. This observation suggests that SNF5 is required for normal nephron development. To validate this assumption, we explore the effect of SNF5 LOF on the NPCs. Indeed, we found that SNF5 LOF significantly affects the spatial organization of the NPCs, and thus prevents their further differentiation into mature nephrons.
Overall, these results show that SNF5 regulates the organization and differentiation of NPCs. Moreover, they suggest that aberrant regulation of the NPCs organization and differentiation due to SNF5 LOF might lead to RT formation.