The planar cell polarity gene Vangl2 is required for mammalian kidney-branching morphogenesis and glomerular maturation

Abstract

The planar cell polarity (PCP) pathway, incorporating non-canonical Wnt signalling, controls embryonic convergent (CE) extension, polarized cell division and ciliary orientation. It also limits diameters of differentiating renal tubules, with mutation of certain components of the pathway causing cystic kidneys. Mutations in mouse Vangl genes encoding core PCP proteins cause neural tube defects (NTDs) and Vangl2 mutations also impair branching of embryonic mouse lung airways. Embryonic metanephric kidneys also undergo branching morphogenesis and Vangl2 is known to be expressed in ureteric bud/collecting duct and metanephric mesenchymal/nephron lineages. These observations led us to investigate metanephroi in Vangl2 mutant mice, Loop-tail (Lp). Although ureteric bud formation is normal in Vangl2Lp/Lp embryos, subsequent in vivo and in vitro branching morphogenesis is impaired. Null mutant kidneys are short, consistent with a CE defect. Differentiating glomerular epithelia express several PCP genes (Vangl1/2, Celsr1, Scrib, Mpk1/2 and Fat4) and glomeruli in Vangl2Lp/Lp fetuses are smaller and contain less prominent capillary loops than wild-type littermates. Furthermore, Vangl2Lp/+ kidneys had modest reduction in glomerular numbers postnatally. Vangl2Lp/Lp metanephroi contained occasional dilated tubules but no overt cystic phenotype. These data show for the first time that a PCP gene is required for normal morphogenesis of both the ureteric bud and metanephric mesenchyme-derived structures. It has long been recognized that certain individuals with NTDs are born with malformed kidneys, and recent studies have discovered VANGL mutations in some NTD patients. On the basis of our mutant mouse study, we suggest that PCP pathway mutations should be sought when NTD and renal malformation co-exist.

Deficiency of the Planar Cell Polarity Protein Vangl2 in Podocytes Affects Glomerular Morphogenesis and Increases Susceptibility to Injury

“…33,34 The PCP pathway also contributes to podocyte biology: Lp 2/2 mice display defects in glomerular morphology and maturation. 22,23 Glomerular defects observed in our new mouse with podocytespecific Vangl2 ablation are reminiscent to those seen in the Lp 2/2 mouse. From the published literature and our observations, we propose that podocytespecific deletion of Vangl2 may affect podocyte development through several mechanisms.…”

“…The knockdown of Vangl2 in cultured mouse podocytes affects filamentous F-actin arrangement and decreases the number of cell protrusions and cell motility 24 ; mild abnormalities in actin distribution in the Lp 2/2 glomerulus were also reported. 22 We, thus, propose that glomerular maturation defects seen in conditional Vangl2 and Lp embryos arise from suboptimal cytoskeletal arrangements within FPs. (2) We recently reported that loss of Vangl2 in cultured cells led to a decrease in nephrin internalization.…”

“…20,21 Detailed analysis of the Vangl2 mutant Looptail (Lp) mouse in our laboratory and by others revealed profound defects in kidney branching morphogenesis and glomerular maturation. 22,23 With respect to the latter, glomeruli in Lp homozygous embryos display a significant developmental delay seen as a predominance of early capillary loop-stage glomeruli compared with the more mature glomerular stages seen in control embryos. 22,23 We also observed significant changes in cell shape, cytoskeletal arrangement, motility, and nephrin endocytosis in cultured podocytes stimulated with a noncanonical PCP Wnt ligand, Wnt5a, or when endogenous Vangl2 was depleted by shRNAs.…”

“…22,23 With respect to the latter, glomeruli in Lp homozygous embryos display a significant developmental delay seen as a predominance of early capillary loop-stage glomeruli compared with the more mature glomerular stages seen in control embryos. 22,23 We also observed significant changes in cell shape, cytoskeletal arrangement, motility, and nephrin endocytosis in cultured podocytes stimulated with a noncanonical PCP Wnt ligand, Wnt5a, or when endogenous Vangl2 was depleted by shRNAs. 23,24 Together, these observations point to the importance of the PCP pathway in podocyte development.…”

Refining the role of Lgl, Dlg and Scrib in Tumor Suppression and Beyond: Learning from the Old Time Classics

“…Apart from regulating the patterning of external epidermal structures such as wing hair cells in Drosophila and ciliary orientation, PCP controls embryonic convergent extension (CE), polarized cell division, cell direction and movement (Yates et al 2010a). dlg, scrib and lgl are essential for planar cell polarity (PCP), by establishing a cross-talk between apical-basal and planar cell polarity.…”