title: Cdkn1c Boosts the Development of Brown Adipose Tissue in a Murine Model of Silver Russell Syndrome.
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.
authors.affiliation: School of Biosciences, Cardiff University, Cardiff, United Kingdom.
authors.forename: Matthew
authors.initials: M
authors.lastname: Van De Pette
authors.affiliation: School of Biosciences, Cardiff University, Cardiff, United Kingdom.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Tunster
authors.affiliation: School of Biosciences, Cardiff University, Cardiff, United Kingdom.
authors.forename: Grainne I
authors.initials: GI
authors.lastname: McNamara
authors.affiliation: School of Biosciences, Cardiff University, Cardiff, United Kingdom.
authors.forename: Tatyana
authors.initials: T
authors.lastname: Shelkovnikova
authors.affiliation: MRC Clinical Sciences Centre, Hammersmith Hospital, London, United Kingdom.
authors.forename: Steven
authors.initials: S
authors.lastname: Millership
authors.affiliation: Nuffield Department of Clinical Neuroscience, Nuffield Laboratory of Ophthalmology, John Radcliffe Hospital, Oxford, United Kingdom.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Benson
authors.affiliation: Nuffield Department of Clinical Neuroscience, Nuffield Laboratory of Ophthalmology, John Radcliffe Hospital, Oxford, United Kingdom.
authors.forename: Stuart
authors.initials: S
authors.lastname: Peirson
authors.affiliation: Division of Translational and Systems Medicine, Warwick Medical School, University of Warwick, Coventry, United Kingdom.
authors.forename: Mark
authors.initials: M
authors.lastname: Christian
authors.affiliation: Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, United Kingdom.
authors.forename: Antonio
authors.initials: A
authors.lastname: Vidal-Puig
authors.affiliation: School of Biosciences, Cardiff University, Cardiff, United Kingdom.
authors.forename: Rosalind M
authors.initials: RM
authors.lastname: John
mesh_terms: D002001:Adipose Tissue, Brown / Q000254:growth & development* / Q000378:metabolism; D052436:Adipose Tissue, White / Q000378:metabolism; D000328:Adult; D000818:Animals; D001831:Body Temperature; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D018392:Genomic Imprinting; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D010641:Phenotype; D056730:Silver-Russell Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: C493965:Cdkn1c protein, mouse; D050761:Cyclin-Dependent Kinase Inhibitor p57; D004268:DNA-Binding Proteins; C521133:Prdm16 protein, mouse; D014157:Transcription Factors