Role of uroplakins in urinary tract development and congenital anomalies of the kidney and urinary tract (CAKUT)
CAKUT are developmental disorders that occur in 1 out of every 500 live births, yet the cellular or molecular basis of these malformations is not well understood. One gene targeted in CAKUT is UPK3a, which encodes the type I transmembrane protein uroplakin 3a (UPK3a). For example, a substitution of a Pro residue for Leu (P273L) in the cytoplasmic domain of human UPK3a leads to renal adysplasia and other urinary tract defects. To better understand why UPK3a expression is important, we have examined the function of Upk3l (aka UPK3d), the UPK3a-like ortholog in zebrafish. Upk3l is expressed at the apical surfaces of the pronephric tubule-associated epithelial cells that form the zebrafish larval urinary tract (i.e., pronephros). Strikingly, loss of Upk3l expression leads to altered epithelial differentiation, including the aberrant expression and distribution of polarity proteins, as well as defects in morphogenesis, including loss of apical microvilli. Current projects in the lab include determining whether UPK3a/Upk3l interacts with Par polarity proteins, identifying how polarity proteins contribute to the formation of the microvillar brush border, and defining whether the P273L mutation of UPK3a causes disease as a result of aberrant and/or defective