Imperial College London
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Dr Steven J. Millership

Faculty of Medicine, Department of Metabolism, Digestion and Reproduction

Research Fellow
 
 
 
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Contact

 

+44 (0)20 7594 3110s.millership Website

 
 
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Location

 

323ICTEM buildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Van:2016:10.1371/journal.pgen.1005916,
author = {Van, De Pette M and Tunster, SJ and McNamara, GI and Shelkovnikova, T and Millership, S and Benson, L and Peirson, S and Christian, M and Vidal-Puig, A and John, RM},
doi = {10.1371/journal.pgen.1005916},
journal = {PLoS Genetics},
title = {Cdkn1c boosts the development of brown adipose tissue in a murine model of Silver Russell syndrome.},
url = {http://dx.doi.org/10.1371/journal.pgen.1005916},
volume = {12},
year = {2016}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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 ge
AU  - Van,De Pette M
AU  - Tunster,SJ
AU  - McNamara,GI
AU  - Shelkovnikova,T
AU  - Millership,S
AU  - Benson,L
AU  - Peirson,S
AU  - Christian,M
AU  - Vidal-Puig,A
AU  - John,RM
DO  - 10.1371/journal.pgen.1005916
PY  - 2016///
SN  - 1553-7390
TI  - Cdkn1c boosts the development of brown adipose tissue in a murine model of Silver Russell syndrome.
T2  - PLoS Genetics
UR  - http://dx.doi.org/10.1371/journal.pgen.1005916
UR  - https://www.ncbi.nlm.nih.gov/pubmed/26963625
UR  - http://hdl.handle.net/10044/1/61410
VL  - 12
ER  -
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