Acute kidney injury and aberrant planar cell polarity induce cyst formation in mice lacking renal cilia.
ABSTRACT Polycystic kidney disease (PKD) is an inherited disorder that is characterized by the accumulation of cysts in the renal parenchyma and progressive decline in renal function. Recent studies suggest that PKD arises from abnormalities of the primary cilium. We have previously shown that kidney-specific inactivation of the ciliogenic gene Kif3a during embryonic development produces kidney cysts and renal failure. Here, we used tamoxifen-inducible, kidney-specific gene targeting to inactivate Kif3a in the postnatal mouse kidney. Kidney-specific inactivation of Kif3a in newborn mice resulted in the loss of primary cilia and produced kidney cysts primarily in the loops of Henle, whereas inactivation in adult mice did not lead to the rapid development of cysts despite a comparable loss of primary cilia. The age-dependence and locations of the cysts suggested that cyst formation required increased rates of cell proliferation. To test this possibility, we stimulated cell proliferation in the adult kidney by inducing acute kidney injury and tubular regeneration. Acute kidney injury induced cyst formation in adult Kif3a mutant mice. Analysis of pre-cystic tubules in Kif3a mutant mice showed that the loss of cilia did not stimulate cell proliferation but instead resulted in aberrant planar cell polarity as manifested by abnormalities in the orientation of cell division. We conclude that primary cilia are required for the maintenance of planar cell polarity in the mammalian kidney and that acute kidney injury exacerbates cystic disease.
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ABSTRACT: Wnt signaling is a well conserved pathway critical for growth, patterning and differentiation of multiple tissues and organs. Previous studies on Wnt signaling in the pancreas have been based predominantly on downstream pathway effector genes such as β-catenin. We here provide evidence that the canonical-pathway member Wnt7b is a physiological regulator of pancreatic progenitor cell growth. Genetic deletion of Wnt7b in the developing pancreas leads to pancreatic hypoplasia due to reduced proliferation of pancreatic progenitor cells during the phase of pancreas development marked by rapid progenitor cell growth. While the differentiation potential of pancreatic progenitor cells is unaffected by Wnt7b deletion, through a gain-of-function analysis, we find that early pancreatic progenitor cells are highly sensitive to Wnt7b expression, but later lose such competence. By modulating the level and the temporal windows of Wnt7b expression we demonstrate a significant impact on organ growth and morphogenesis particularly during the early branching stages of the organ, which negatively affects generation of the pro-endocrine (Ngn3+/Nkx6.1+), and pro-acinar (Ptf1A+) fields. Consequently, Wnt7b gain-of-function results in failed morphogenesis and almost complete abrogation of the differentiation of endocrine and acinar cells, leading to cystic epithelial metaplasia expressing ductal markers including Sox9, Hnf6 and Hnf1β. While Wnt7b is expressed exclusively in the developing pancreatic epithelium, adjacent mesenchymal cells in the organ display a direct trophic response to elevated Wnt7b and increase expression of Lef1, cFos and desmin. Of note, in contrast to the pancreatic epithelium, the pancreatic mesenchyme remains competent to respond to Wnt7b ligand, at later stages in development. We conclude that Wnt7b helps coordinate pancreatic development through autocrine, as well as paracrine mechanisms, and as such represents a novel bi-modal morphogen ligand.Developmental Biology 01/2015; · 3.64 Impact Factor
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ABSTRACT: Cilia proteins have long been characterized for their role in cilia formation and function, and their implications in ciliopathies. However, several cellular defects induced by cilia proteins deregulation suggest that they could have non-ciliary roles. Indeed, several non-ciliary functions have been recently characterized for cilia proteins including roles in intra-cellular and in vesicular transport, in spindle orientation or in the maintenance of genomic stability. These observations thus raise the crucial question of the contribution of non-ciliary functions of cilia proteins to the pathological manifestations associated with ciliopathies such as polycystic kidney disease.Médecine sciences : M/S. 11/2014; 30(11):1040-6.
Article: [Cilia and renal cysts].[Show abstract] [Hide abstract]
ABSTRACT: Advances in genomics, bioinformatics and the creation of model organisms have identified many genes associated with polycystic kidney diseases. Historically, these genes were not necessarily associated with ciliopathies, but it appeared that many connections can be made between the cystic kidney disease and function of the primary cilium. Indeed, the proteins encoded by these genes are localized to the cilium itself, to the basal body or are known to regulate the expression and localization of ciliary proteins. The goal of this article is to describe the multiple cellular processes that may lead to the development of renal cysts if they are deregulated. These include changes in proliferation rate, cell polarity or signaling pathways involved in embryonic kidney development. To highlight the role of the primary cilium in cystogenesis, I will discuss several studies investigating the function of ciliary genes and cilia in the kidneys of different model organisms.Médecine sciences : M/S. 11/2014; 30(11):1024-33.