Goggolidou, Paraskevi, Hadjirin, Nazreen F., Bak, Aggie, Papakrivopoulou, Eugenia, Hilton, Helen, Norris, Dominic P. and Dean, Charlotte H. (2014) Atmin mediates kidney morphogenesis by modulating Wnt signaling. Human Molecular Genetics, 23 (20). pp. 5303-5316. ISSN 0964-6906

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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.

Item Type:	Article
Identifier:	10.1093/hmg/ddu246
Additional Information:	© The Author 2014. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords:	signal transduction, cell growth, epithelium, genes, homozygote, morphogenesis, cilia, kidney, mice, kidney development, wnt signaling pathway
Subjects:	Medicine and health Medicine and health > Nursing
Depositing User:	Dominic Walker
Date Deposited:	25 Nov 2016 15:19
Last Modified:	04 Nov 2024 12:15
URI:	https://repository.uwl.ac.uk/id/eprint/2979

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