title: Loss of FTO antagonises Wnt signaling and leads to developmental defects associated with ciliopathies.
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 (Fto(-/-) MEFs and HEK293T). Canonical Wnt signalling is down regulated by abrogated β-Catenin translocation to the nucleus whilst non-canonical Wnt/Ca(2+) pathway is activated via its key signal mediators CaMKII and PKCδ. 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.
authors: Biomedical Sciences, St George's University of London, London, United Kingdom.
authors: Daniel P S
authors: DP
authors: Osborn
authors: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, United Kingdom.
authors: Rosa Maria
authors: RM
authors: Roccasecca
authors: Harwell Science and Innovation Campus, MRC Harwell, Harwell, United Kingdom.
authors: Fiona
authors: F
authors: McMurray
authors: Molecular Medicine Unit, Institute of Child Health, University College London, London, United Kingdom.
authors: Victor
authors: V
authors: Hernandez-Hernandez
authors: Molecular Medicine Unit, Institute of Child Health, University College London, London, United Kingdom.
authors: Sriparna
authors: S
authors: Mukherjee
authors: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, United Kingdom ; University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, United Kingdom.
authors: Inês
authors: I
authors: Barroso
authors: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, United Kingdom.
authors: Derek
authors: D
authors: Stemple
authors: Harwell Science and Innovation Campus, MRC Harwell, Harwell, United Kingdom.
authors: Roger
authors: R
authors: Cox
authors: Molecular Medicine Unit, Institute of Child Health, University College London, London, United Kingdom.
authors: Philip L
authors: PL
authors: Beales
authors: Molecular Medicine Unit, Institute of Child Health, University College London, London, United Kingdom.
authors: Sonia
authors: S
authors: Christou-Savina
mesh_terms: D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D000818:Animals; D020013:Calcium Signaling; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002460:Cell Line; D002923:Cilia / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D000013:Congenital Abnormalities / Q000235:genetics* / Q000378:metabolism*; D004789:Enzyme Activation; D005260:Female; D055786:Gene Knockout Techniques; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009024:Morphogenesis / Q000235:genetics; D009928:Organ Specificity / Q000235:genetics; D010641:Phenotype; D011506:Proteins / Q000235:genetics*; D060449:Wnt Signaling Pathway; D015027:Zebrafish; D051176:beta Catenin / Q000378:metabolism
chemical_list: D011506:Proteins; D051176:beta Catenin; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2