Abstract
The DNA damage protein and transcription factor Atmin (Asciz) is required for both lung tubulogenesis and ciliogenesis. Like the lungs, kidneys contain a tubular network that is critical for their function and in addition, renal ciliary dysfunction has been implicated in the pathogenesis of cystic kidney disease. Using the Atmin mouse mutant Gasping6 (Gpg6), we investigated kidney development and found it severely disrupted with reduced branching morphogenesis, resulting in fewer epithelial structures being formed. Unexpectedly, transcriptional levels of key cilia associated genes were not altered in AtminGpg6/Gpg6 kidneys. Instead, Gpg6 homozygous kidneys exhibited altered cytoskeletal organization and modulation of Wnt signaling pathway molecules, including β-catenin and non-canonical Wnt/planar cell polarity (PCP) pathway factors, such as Daam2 and Vangl2. Wnt signaling is important for kidney development and perturbation of Wnt signaling pathways can result in cystic, and other, renal abnormalities. In common with other PCP pathway mutants, AtminGpg6/Gpg6 mice displayed a shortened rostral-caudal axis and mis-oriented cell division. Moreover, intercrosses between AtminGpg6/+ and Vangl2Lp/+ mice revealed a genetic interaction between Atmin and Vangl2. Thus we show for the first time that Atmin is critical for normal kidney development and we present evidence that mechanistically, Atmin modifies Wnt signaling pathways, specifically placing it as a novel effector molecule in the non-canonical Wnt/PCP pathway. The identification of a novel modulator of Wnt signaling has important implications for understanding the pathobiology of renal disease.
Highlights
Tissue morphogenesis is a critical component of all stages of kidney development and disruption of any of these steps can lead to a variety of developmental defects that impact on kidney function [1,2]
Studies have shown that AtminGpg6/Gpg6 embryos die around E14 and display a phenotype indicative of a complex ciliopathy including gross edema, exencephaly and left-right patterning defects [31]
Wnts are required for many aspects of kidney development and homeostasis; the planar cell polarity (PCP) pathway branch regulates morphogenesis of metanephric mesenchyme and ureteric bud-derived structures, including podocytes, through cytoskeleton reorganization/rearrangement [9,11,12]
Summary
Tissue morphogenesis is a critical component of all stages of kidney development and disruption of any of these steps can lead to a variety of developmental defects that impact on kidney function [1,2]. Reciprocal signaling between mesenchymal and epithelial cells promotes branching morphogenesis of the ureteric bud, eventually leading to the establishment of nephrogenic progenitors and their subsequent differentiation into mature nephrons containing glomeruli [3,4]. A key function of the PCP pathway is modification of the actin-myosin cytoskeleton to enable morphogenetic movement of tissue, shaping of cells and/or directed cell migration, all of which are critical for normal development and optimum organ function [9,10,11,12,13]. Perturbation of directed cell movements during tubule morphogenesis, podocyte development and the orientation of cell division and cell adhesion have all been related to defective PCP [14,15]. Mutations in the PCP-associated genes Wnt9b and Fat have been shown to lead to cyst formation in
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