Loss of FTO antagonises Wnt signaling and leads to developmental defects associated with ciliopathies.
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. Despi...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2014-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3913654?pdf=render |
| _version_ | 1818923766027124736 |
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| author | Daniel P S Osborn Rosa Maria Roccasecca Fiona McMurray Victor Hernandez-Hernandez Sriparna Mukherjee Inês Barroso Derek Stemple Roger Cox Philip L Beales Sonia Christou-Savina |
| author_facet | Daniel P S Osborn Rosa Maria Roccasecca Fiona McMurray Victor Hernandez-Hernandez Sriparna Mukherjee Inês Barroso Derek Stemple Roger Cox Philip L Beales Sonia Christou-Savina |
| author_sort | Daniel P S Osborn |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-20T02:14:39Z |
| format | Article |
| id | doaj.art-15ec4825de684ab1ae0924d982466a44 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-20T02:14:39Z |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-15ec4825de684ab1ae0924d982466a442022-12-21T19:56:58ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0192e8766210.1371/journal.pone.0087662Loss of FTO antagonises Wnt signaling and leads to developmental defects associated with ciliopathies.Daniel P S OsbornRosa Maria RoccaseccaFiona McMurrayVictor Hernandez-HernandezSriparna MukherjeeInês BarrosoDerek StempleRoger CoxPhilip L BealesSonia Christou-SavinaCommon 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.http://europepmc.org/articles/PMC3913654?pdf=render |
| spellingShingle | Daniel P S Osborn Rosa Maria Roccasecca Fiona McMurray Victor Hernandez-Hernandez Sriparna Mukherjee Inês Barroso Derek Stemple Roger Cox Philip L Beales Sonia Christou-Savina Loss of FTO antagonises Wnt signaling and leads to developmental defects associated with ciliopathies. PLoS ONE |
| title | Loss of FTO antagonises Wnt signaling and leads to developmental defects associated with ciliopathies. |
| title_full | Loss of FTO antagonises Wnt signaling and leads to developmental defects associated with ciliopathies. |
| title_fullStr | Loss of FTO antagonises Wnt signaling and leads to developmental defects associated with ciliopathies. |
| title_full_unstemmed | Loss of FTO antagonises Wnt signaling and leads to developmental defects associated with ciliopathies. |
| title_short | Loss of FTO antagonises Wnt signaling and leads to developmental defects associated with ciliopathies. |
| title_sort | loss of fto antagonises wnt signaling and leads to developmental defects associated with ciliopathies |
| url | http://europepmc.org/articles/PMC3913654?pdf=render |
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