Partitioning-Defective 1a/b Depletion Impairs Glomerular and Proximal Tubule Development

The kidney is a highly polarized epithelial organ that develops from undifferentiated mesenchyme, although the mechanisms that regulate the development of renal epithelial polarity are incompletely understood. Partitioning-defective 1 (Par1) proteins have been implicated in cell polarity and epithelial morphogenesis; however, the role of these proteins in the developing kidney has not been established. Therefore, we studied the contribution of Par1 a/b to renal epithelial development. We examined the renal phenotype of newborn compound mutant mice carrying only one allele of Par1 a or Par1 b. Loss of three out of four Par1 a/b alleles resulted in severe renal hypoplasia, associated with impaired ureteric bud branching. Compared with kidneys of newborn control littermates, kidneys of newborn mutant mice exhibited dilated proximal tubules and immature glomeruli, and the renal proximal tubular epithelia lacked proper localization of adhesion complexes. Furthermore, Par1 a/b mutants expressed low levels of renal Notch ligand Jag1, activated Notch2, and Notch effecter Hest. Together, these data demonstrate that Part a/b has a key role in glomerular and proximal tubule development, likely via modulation of Notch signaling.