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Cdkn1c boosts the development of brown adipose tissue in a murine model of Silver Russell syndrome

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Van De Pette, Matthew, Tunster, Simon J., McNamara, Grainne I., Shelkovnikova, Tatyana, Millership, Steven, Benson, Lindsay, Peirson, Stuart, Christian, Mark, Vidal-Puig, Antonio and John, Rosalind M. (2016) Cdkn1c boosts the development of brown adipose tissue in a murine model of Silver Russell syndrome. PLoS Genetics, 12 (3). e1005916. doi:10.1371/journal.pgen.1005916 ISSN 1553-7390.

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Official URL: http://dx.doi.org/10.1371/journal.pgen.1005916

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Abstract

The accurate diagnosis and clinical management of the growth restriction disorder Silver Russell Syndrome (SRS) has confounded researchers and clinicians for many years due to the myriad of genetic and epigenetic alterations reported in these patients and the lack of suitable animal models to test the contribution of specific gene alterations. Some genetic alterations suggest a role for increased dosage of the imprinted CYCLIN DEPENDENT KINASE INHIBITOR 1C (CDKN1C) gene, often mutated in IMAGe Syndrome and Beckwith-Wiedemann Syndrome (BWS). Cdkn1c encodes a potent negative regulator of fetal growth that also regulates placental development, consistent with a proposed role for CDKN1C in these complex childhood growth disorders. Here, we report that a mouse modelling the rare microduplications present in some SRS patients exhibited phenotypes including low birth weight with relative head sparing, neonatal hypoglycemia, absence of catch-up growth and significantly reduced adiposity as adults, all defining features of SRS. Further investigation revealed the presence of substantially more brown adipose tissue in very young mice, of both the classical or canonical type exemplified by interscapular-type brown fat depot in mice (iBAT) and a second type of non-classic BAT that develops postnatally within white adipose tissue (WAT), genetically attributable to a double dose of Cdkn1c in vivo and ex-vivo. Conversely, loss-of-function of Cdkn1c resulted in the complete developmental failure of the brown adipocyte lineage with a loss of markers of both brown adipose fate and function. We further show that Cdkn1c is required for post-transcriptional accumulation of the brown fat determinant PR domain containing 16 (PRDM16) and that CDKN1C and PRDM16 co-localise to the nucleus of rare label-retaining cell within iBAT. This study reveals a key requirement for Cdkn1c in the early development of the brown adipose lineages. Importantly, active BAT consumes high amounts of energy to generate body heat, providing a valid explanation for the persistence of thinness in our model and supporting a major role for elevated CDKN1C in SRS.

Item Type: Journal Article
Subjects: R Medicine > RJ Pediatrics
Divisions: Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Cell & Developmental Biology
Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences
Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH): Growth disorders -- Diagnosis, Growth disorders -- Treatment, Adipose tissues
Journal or Publication Title: PLoS Genetics
Publisher: Public Library of Science
ISSN: 1553-7390
Official Date: 10 March 2016
Dates:
DateEvent
10 March 2016Published
14 February 2016Accepted
Volume: 12
Number: 3
Article Number: e1005916
DOI: 10.1371/journal.pgen.1005916
Status: Peer Reviewed
Publication Status: Published
Date of first compliant deposit: 13 January 2017
Date of first compliant Open Access: 16 January 2017
Funder: Biotechnology and Biological Sciences Research Council (Great Britain) (BBSRC), Medical Research Council (Great Britain) (MRC)
Grant number: BB/F016557, BB/J015156 (BBSRC), MR/M013960/1 (MRC)

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