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Polycystic kidney disease (PKD) is the most common genetic cause of renal failure in humans. Several proteins that are encoded by genes associated with PKD have recently been identified in primary cilia in renal tubular epithelia. These findings have suggested that abnormalities in cilia formation and function may play a role in the pathogenesis of PKD. To directly determine whether cilia are essential to maintain tubular integrity, we conditionally inactivated KIF3A, a subunit of kinesin-II that is essential for cilia formation, in renal epithelia. Constitutive inactivation of KIF3A produces abnormalities of left-right axis determination and embryonic lethality. Here we show that tissue-specific inactivation of KIF3A in renal tubular epithelial cells results in viable offspring with normal-appearing kidneys at birth. Cysts begin to develop in the kidney at postnatal day 5 and cause renal failure by postnatal day 21. The cyst epithelial cells lack primary cilia and exhibit increased proliferation and apoptosis, apical mislocalization of the epidermal growth factor receptor, increased expression of beta-catenin and c-Myc, and inhibition of p21(CIP1). These results demonstrate that the absence of renal cilia produces both the clinical and cell biological findings associated with PKD. Most generally, the phenotype of Kif3a mutant mice suggests a role for primary cilia in the maintenance of lumen-forming epithelial differentiation.
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http://dx.doi.org/10.1073/pnas.0836980100 | DOI Listing |
Kidney Int
November 2024
III. Department of Medicine, University Hospital Hamburg Eppendorf, Hamburg, Germany; Hamburg Center for Kidney Health (HCKH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Progression of cystic kidney disease has been linked to activation of the mTORC1 signaling pathway. Yet the utility of mTORC1 inhibitors to treat patients with polycystic kidney disease remains controversial despite promising preclinical data. To define the cell intrinsic role of mTORC1 for cyst development, the mTORC1 subunit gene Raptor was selectively inactivated in kidney tubular cells lacking cilia due to simultaneous deletion of the kinesin family member gene Kif3A.
View Article and Find Full Text PDFCell Mol Gastroenterol Hepatol
October 2022
University of Arizona College of Medicine, Department of Medicine, Division of Gastroenterology, Tucson, Arizona. Electronic address:
Background & Aims: Efforts to characterize the signaling mechanisms that underlie gastroenteropancreatic neoplasms (GEP-NENs) are precluded by a lack of comprehensive models that recapitulate pathogenesis. Investigation into a potential cell-of-origin for gastrin-secreting NENs revealed a non-cell autonomous role for loss of menin in neuroendocrine cell specification, resulting in an induction of gastrin in enteric glia. Here, we investigated the hypothesis that cell autonomous Men1 inactivation in glial fibrillary acidic protein (GFAP)-expressing cells induced neuroendocrine differentiation and tumorigenesis.
View Article and Find Full Text PDFJCI Insight
May 2021
Department of C&M Physiology and.
Flow-activated Na+ and HCO3- transport in kidney proximal tubules (PT) underlies relatively constant fractional reabsorption during changes in glomerular filtration rate (GFR) or glomerulotubular balance (GTB). In view of hypothesized connections of epithelial cilia to flow sensing, we examined flow-activated transport in 3 polycystic kidney disease-related mouse models based on inducible conditional KO of Pkd1, Pkd2, and Kif3a. PTs were harvested from mice after gene inactivation but prior to cyst formation, and flow-mediated PT transport was measured.
View Article and Find Full Text PDFJ Clin Invest
August 2020
Hudson Institute of Medical Research, Clayton, Victoria, Australia.
Ligand-dependent activation of Hedgehog (Hh) signaling in cancer occurs without mutations in canonical pathway genes. Consequently, the genetic basis of Hh pathway activation in adult solid tumors, such as small-cell lung cancer (SCLC), is unknown. Here we show that combined inactivation of Trp53 and Rb1, a defining genetic feature of SCLC, leads to hypersensitivity to Hh ligand in vitro, and during neural tube development in vivo.
View Article and Find Full Text PDFJ Cell Sci
September 2018
Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India 560 012
Sorting endosomes (SEs) are the regulatory hubs for sorting cargo to multiple organelles, including lysosome-related organelles, such as melanosomes in melanocytes. In parallel, melanosome biogenesis is initiated from SEs with the processing and sequential transport of melanocyte-specific proteins toward maturing melanosomes. However, the mechanism of cargo segregation on SEs is largely unknown.
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