平衡
输尿管
肾脏发育
胚胎干细胞
肾
细胞生物学
上皮
胚胎发生
生物
医学
内分泌学
胚胎
泌尿科
病理
基因
遗传学
作者
Kelsey R. Clearman,Napassawon Timpratoom,D.J. Patel,Addison Rains,Courtney J. Haycraft,Mandy J. Croyle,Jeremy F. Reiter,Bradley K. Yoder
出处
期刊:Journal of The American Society of Nephrology
日期:2024-03-26
标识
DOI:10.1681/asn.0000000000000335
摘要
Background: Rab35 is a member of a GTPase family of endocytic trafficking proteins. Studies in cell lines have indicated that Rab35 participates in cell adhesion, polarity, cytokinesis, and primary cilia length and composition. Additionally, sea urchin Rab35 regulates actin organization and is required for gastrulation. In mice, loss of Rab35 in the CNS disrupts hippocampal development and neuronal organization. Outside of the CNS, the functions of mammalian Rab35 in vivo are unknown. Methods: We generated and analyzed the consequences of both congenital and conditional null Rab35 mutations in mice. Using a LacZ reporter allele, we assessed Rab35 expression during development and postnatally. We assessed Rab35 loss in the kidney and ureter using histology, immunofluorescence microscopy, and western blotting. Results: Congenital Rab35 loss of function caused embryonic lethality: homozygous mutants arrested at E7.5 with cardiac edema. Conditional loss of Rab35, either during gestation or postnatally, caused hydronephrosis. The kidney and ureter phenotype were associated with disrupted actin cytoskeletal architecture, altered Arf6 epithelial polarity, reduced adherens junctions, loss of tight junction formation, defects in EGFR expression and localization, disrupted cell differentiation, and shortened primary cilia. Conclusions: Rab35 is essential for mammalian development and the maintenance of kidney and ureter architecture. Loss of Rab35 leads to non-obstructive hydronephrosis, making the Rab35 mutant mouse a novel mammalian model to study mechanisms underlying this disease.
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