Atmin mediates kidney morphogenesis by modulating Wnt signaling.
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 Atmin(Gpg6/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, Atmin(Gpg6/Gpg6) mice displayed a shortened rostral-caudal axis and mis-oriented cell division. Moreover, intercrosses between Atmin(Gpg6/+) and Vangl2(Lp/+) 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.
Leukocyte Biology, National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK c.dean@imperial.ac.uk p.goggolidou@open.ac.uk.
Paraskevi
P
Goggolidou
Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge CB3 0ES, UK.
Nazreen F
NF
Hadjirin
College of Nursing, Midwifery & Healthcare, University of West London, Middlesex TW8 9GB, UK.
Aggie
A
Bak
Nephro-Urology Unit, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK.
Eugenia
E
Papakrivopoulou
Mammalian Genetics Unit, Medical Research Council, Harwell, UK.
Helen
H
Hilton
Mammalian Genetics Unit, Medical Research Council, Harwell, UK.
Dominic P
DP
Norris
Leukocyte Biology, National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK Mammalian Genetics Unit, Medical Research Council, Harwell, UK c.dean@imperial.ac.uk p.goggolidou@open.ac.uk.
Charlotte H
CH
Dean
D000818:Animals; D002923:Cilia / Q000235:genetics / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D004622:Embryo, Mammalian / Q000473:pathology; D018507:Gene Expression Regulation, Developmental; D007668:Kidney / Q000254:growth & development* / Q000473:pathology; D007674:Kidney Diseases / Q000196:embryology* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D060449:Wnt Signaling Pathway
C554480:ATMIN protein, mouse; C431577:Ltap protein, mouse; D009419:Nerve Tissue Proteins; D014157:Transcription Factors