Abstract
Planar cell polarity (PCP) pathway is crucial for tissue morphogenesis. Mutations in PCP genes cause multi-organ anomalies including dysplastic kidneys. Defective PCP signaling was postulated to contribute to cystogenesis in polycystic kidney disease. This work was undertaken to elucidate the role of the key PCP gene, Vangl2, in embryonic and postnatal renal tubules and ascertain whether its loss contributes to cyst formation and defective tubular function in mature animals. We generated mice with ubiquitous and collecting duct-restricted excision of Vangl2. We analyzed renal tubules in mutant and control mice at embryonic day E17.5 and postnatal days P1, P7, P30, P90, 6- and 9-month old animals. The collecting duct functions were analyzed in young and adult mutant and control mice. Loss of Vangl2 leads to profound tubular dilatation and microcysts in embryonic kidneys. Mechanistically, these abnormalities are caused by defective convergent extension (larger tubular cross-sectional area) and apical constriction (cuboidal cell shape and a reduction of activated actomyosin at the luminal surface). However, the embryonic tubule defects were rapidly resolved by Vangl2-independent mechanisms after birth. Normal collecting duct architecture and functions were found in young and mature animals. During embryogenesis, Vangl2 controls tubular size via convergent extension and apical constriction. However, rapidly after birth, PCP-dependent control of tubular size is switched to a PCP-independent regulatory mechanism. We conclude that loss of the Vangl2 gene is dispensable for tubular elongation and maintenance postnatally. It does not lead to cyst formation and is unlikely to contribute to polycystic kidney disease.
Highlights
Congenital anomalies of the kidney and urinary tract (CAKUT) are a subset of birth defects comprising 20–30% of prenatally-identified malformations [1]
Tubulogenesis depends on the Planar cell polarity (PCP) pathway-controlled convergent extension (CE) process; disruption of CE leads to tubular shortening and dilatation [13]
As evidenced by a significantly larger average cross-sectional area and a higher cell number in both the Lotus tetragonolobus (LTA)(+) and DBA(+) tubules in the Vangl2Lp/Lp compared to wildtype kidneys, CE was disrupted in the mutant proximal tubules (Fig 1C) and collecting ducts (Fig 1D); mutant area distribution was wider in range and skewed towards a larger size (Fig 1E)
Summary
Congenital anomalies of the kidney and urinary tract (CAKUT) are a subset of birth defects comprising 20–30% of prenatally-identified malformations [1]. Fischer et al described uniform orientation of cell division (OCD) in the growing renal tubules of young mice and rats; OCD was lost in postnatal rodent models of polycystic kidney disease [14] This discovery paved the way to the postulate that defective PCP signaling randomizes OCD and contributes to renal tubule dilatation and/or cyst initiation [15]. To assess the requirement for PCP signaling during kidney development, for postnatal tubular modeling and in adult tubular maintenance, we generated mutant mouse strains with ubiquitous and collecting duct-restricted excision of the Vangl gene. Our study establishes differential requirements for Vangl before and after birth It refutes the proposed cystogenic role for defective PCP signaling in polycystic kidney disease
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