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Loss of FTO Antagonises Wnt Signaling and Leads to Developmental Defects Associated with Ciliopathies

Osborn, DP; Roccasecca, RM; McMurray, F; Hernandez-Hernandez, V; Mukherjee, S; Barroso, I; Stemple, D; Cox, R; Beales, PL; Christou-Savina, S (2014) Loss of FTO Antagonises Wnt Signaling and Leads to Developmental Defects Associated with Ciliopathies. PLOS ONE, 9 (2). e87662 (1)- e87662 (13). ISSN 1932-6203 https://doi.org/10.1371/journal.pone.0087662
SGUL Authors: Osborn, Daniel Peter Sayer

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Abstract

Common intronic variants in the Human fat mass and obesity-associated gene (FTO) are found to be associated with an increased risk of obesity. Overexpression of FTO correlates with increased food intake and obesity, whilst loss-of-function results in lethality and severe developmental defects. Despite intense scientific discussions around the role of FTO in energy metabolism, the function of FTO during development remains undefined. Here, we show that loss of Fto leads to developmental defects such as growth retardation, craniofacial dysmorphism and aberrant neural crest cells migration in Zebrafish. We find that the important developmental pathway, Wnt, is compromised in the absence of FTO, both in vivo(zebrafish) and in vitro (Fto2/2 MEFs and HEK293T). Canonical Wnt signalling is down regulated by abrogated b-Catenin translocation to the nucleus whilst non-canonical Wnt/Ca2+ pathway is activated via its key signal mediators CaMKII and PKCd. Moreover, we demonstrate that loss of Fto results in short, absent or disorganised cilia leading to situs inversus, renal cystogenesis, neural crest cell defects and microcephaly in Zebrafish. Congruently, Fto knockout mice display aberrant tissue specific cilia. These data identify FTO as a protein-regulator of the balanced activation between canonical and non-canonical branches of the Wnt pathway. Furthermore, we present the first evidence that FTO plays a role in development and cilia formation/function.

Item Type: Article
Additional Information: Copyright: 2014 Osborn et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Keywords: Science & Technology, Multidisciplinary Sciences, Science & Technology - Other Topics, MULTIDISCIPLINARY SCIENCES, ZEBRAFISH KUPFFERS VESICLE, LEFT-RIGHT ASYMMETRY, NEURAL CREST, CHOROID-PLEXUS, ADULT OBESITY, CAMK-II, CILIA, GENE, HEDGEHOG, MOUSE, General Science & Technology, MD Multidisciplinary
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) > Cell Sciences (INCCCS)
Journal or Publication Title: PLOS ONE
ISSN: 1932-6203
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Dates:
DateEvent
4 February 2014Published
Web of Science ID: WOS:000330631800057
URI: https://openaccess.sgul.ac.uk/id/eprint/107059
Publisher's version: https://doi.org/10.1371/journal.pone.0087662

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