Jagged1 and kidney vascular development

Renal vascular development is dependent on the participation of renin precursor cells, which localize to areas of new vessel formation and differentiate into smooth muscle cells (SMCs), mesangial and JG cells. However, the mechanisms that enforce this particular fate of renin precursor cells remain unclear. The Notch signaling pathway is involved in the regulation of vascular development. Dr. Gomez’s laboratory has previously shown that during embryogenesis, renin cells express a significant number of angiogenic factors including Notch receptors and their ligands. Notable among these factors is Jagged 1, which is highly expressed in renin cell precursors suggesting that it may specify renin cells to a SMC cell, JG cell and/or a mesangial cell fate.  We therefore hypothesize that Jagged1 is necessary for renin precursors to differentiate into the various mural cells of the renal arterioles and that Jagged1 plays a critical role in renal vascular development. We propose to: 1) characterize the expression pattern of Jagged 1 along the kidney vasculature at different times during development, and 2) determine whether conditional Jagged1 deletion in the renin cell lineage alters the differentiation of renin cell precursors to arterial SMCs, mesangial cells and JG cells and overall renal vascular development, including branching pattern and elongation. We predict that Jagged 1 is required for activation of the Notch signaling pathway in the renin cell lineage and that continuous expression is necessary for maintaining cell fate and plasticity. Lack of Jagged 1 may lead to downregulation of the Notch signaling pathway in renin cells and ultimately loss of their ability to differentiate into multiple cell fates including vascular SMCs, mesangial cells, and JG cells. The proposed experiments should yield significant and relevant information to our understanding of renal vascular development and form the basis for an independent grant proposal.