Imprinted Gene Dosage Is Critical for the Transition to Independent Life

Marika Charalambous,Sacramento R Ferron,Simao T Da Rocha,Andrew J Murray,Timothy Rowland,Mitsuteru Ito,Karin Schuster-Gossler,Arturo Hernandez,Anne C Ferguson-Smith

doi:10.1016/j.cmet.2012.01.006

Marika Charalambous, Sacramento R Ferron + Show 7 more

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https://doi.org/10.1016/j.cmet.2012.01.006

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Abstract

SummaryNeonatal survival in mammals is crucially dependent upon maintenance of body temperature. Neonatal body temperature is largely maintained by thermogenesis in brown adipose tissue (BAT). BAT develops perinatally in mice requiring integration of adipogenic and thermoregulatory gene pathways. We describe a regulatory mutation in the imprinted gene cluster on mouse chromosome 12 resulting in early postnatal lethality. Maternal inheritance of this mutation impairs the ability of young mice to maintain body temperature. While mechanisms of perinatal BAT development are well understood, our work highlights a second phase of BAT recruitment necessary to support small animals newly independent of the nest. We show that the imprinted delta-like homolog 1/preadipocyte factor (Dlk1/Pref1) and iodothyronine deiodinase type 3 (Dio3) functions converge on the development of brown fat at the transition to independent life. This shows that appropriate dosage control at imprinted loci can act as a critical determinant in postnatal survival during phases of physiological adaptation.

Highlights

Imprinting arose in mammals coincidently with the evolution of homothermy and placentation (Edwards et al, 2007)
A recent study demonstrated that both Dlk1 and deiodinase type 3 (Dio3) expression was elevated in cultured brown preadipocytes and downregulated during differentiation, suggesting that imprinting might control the dosage of these genes to regulate thermogenesis (Hernandez et al, 2007)
We have previously described several genetic models that result in the complete loss of imprinting at mouse chromosome 12, such that Dlk1, Rtl1 and Dio3 are fully expressed from both parental alleles and noncoding RNA expression was repressed

Summary

Introduction

Imprinting (i.e., the differential expression of a gene depending upon its parental origin) arose in mammals coincidently with the evolution of homothermy and placentation (Edwards et al, 2007). The linkage of Dlk and Dio precedes the evolution of imprinting, and synteny is conserved in fish and birds (Edwards et al, 2008). This suggests that the genes are functionally linked (Fredman et al, 2009) and that selection has later acted to coordinately control their dosage by imprinting. A recent study demonstrated that both Dlk and Dio expression was elevated in cultured brown preadipocytes and downregulated during differentiation, suggesting that imprinting might control the dosage of these genes to regulate thermogenesis (Hernandez et al, 2007). A role for Dlk in preweaning BAT differentiation in vivo has not been established

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