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An imprinted gene network that controls mammalian somatic growth is down-regulated during postnatal growth deceleration in multiple organs.

ABSTRACT: In mammals, somatic growth is rapid in early postnatal life but decelerates with age and eventually halts, thus determining the adult body size of the species. This growth deceleration, which reflects declining proliferation, occurs simultaneously in multiple organs yet appears not to be coordinated by a systemic mechanism. We, therefore, hypothesized that growth deceleration results from a growth-limiting genetic program that is common to multiple tissues. Here, we identified a set of 11 imprinted genes that show down-regulation of mRNA expression with age in multiple organs. For these genes, Igf2, H19, Plagl1, Mest, Peg3, Dlk1, Gtl2, Grb10, Ndn, Cdkn1c, and SLC38a4, the declines show a temporal pattern similar to the decline in growth rate. All 11 genes have been implicated in the control of cell proliferation or somatic growth. Thus, our findings suggest that the declining expression of these genes contributes to coordinate growth deceleration in multiple tissues. We next hypothesized that the coordinate decline in expression of these imprinted genes is caused by altered methylation and consequent silencing of the expressed allele. Contrary to this hypothesis, the methylation status of the promoter regions of Mest, Peg3, and Plagl1 did not change with age. Our findings suggest that a set of growth-regulating imprinted genes is expressed at high levels in multiple tissues in early postnatal life, contributing to rapid somatic growth, but that these genes are subsequently downregulated in multiple tissues simultaneously, contributing to coordinate growth deceleration and cessation, thus imposing a fundamental limit on adult body size.

SUBMITTER: Lui JC

PROVIDER: S-EPMC2494817 | biostudies-other | 2008 Jul

REPOSITORIES: biostudies-other

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An imprinted gene network that controls mammalian somatic growth is down-regulated during postnatal growth deceleration in multiple organs.

Lui Julian C JC Finkielstain Gabriela P GP Barnes Kevin M KM Baron Jeffrey J

American journal of physiology. Regulatory, integrative and comparative physiology 20080430 1

In mammals, somatic growth is rapid in early postnatal life but decelerates with age and eventually halts, thus determining the adult body size of the species. This growth deceleration, which reflects declining proliferation, occurs simultaneously in multiple organs yet appears not to be coordinated by a systemic mechanism. We, therefore, hypothesized that growth deceleration results from a growth-limiting genetic program that is common to multiple tissues. Here, we identified a set of 11 imprin ...[more]

PMID: 18448610

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Project description:Homozygous mutation of the Csf1r locus (Csf1rko) in mice, rats and humans leads to multiple postnatal developmental abnormalities. To enable analysis of the mechanisms underlying the phenotypic impacts of Csf1r mutation, we bred a rat Csf1rko allele to the inbred dark agouti (DA) genetic background and to a Csf1r-mApple reporter transgene. The Csf1rko led to almost complete loss of embryonic macrophages and ablation of most adult tissue macrophage populations. We extended previous analysis of the Csf1rko phenotype to early postnatal development to reveal impacts on musculoskeletal development and proliferation and morphogenesis in multiple organs. Expression profiling of 3-week old wild-type (WT) and Csf1rko livers identified 2760 differentially expressed genes associated with the loss of macrophages, severe hypoplasia, delayed hepatocyte maturation, disrupted lipid metabolism and the IGF1/IGF binding protein system. Older Csf1rko rats developed severe hepatic steatosis. Consistent with the developmental delay in the liver Csf1rko rats had greatly-reduced circulating IGF1. Transfer of WT bone marrow (BM) cells at weaning without conditioning repopulated resident macrophages in all organs, including microglia in the brain, and reversed the mutant phenotypes enabling long term survival and fertility. WT BM transfer restored osteoclasts, eliminated osteopetrosis, restored bone marrow cellularity and architecture and reversed granulocytosis and B cell deficiency. Csf1rko rats had an elevated circulating CSF1 concentration which was rapidly reduced to WT levels following BM transfer. However, CD43hi non-classical monocytes, absent in the Csf1rko, were not rescued and bone marrow progenitors remained unresponsive to CSF1. The results demonstrate that the Csf1rko phenotype is autonomous to BM-derived cells and indicate that BM contains a progenitor of tissue macrophages distinct from hematopoietic stem cells. The model provides a unique system in which to define the pathways of development of resident tissue macrophages and their local and systemic roles in growth and organ maturation.

Dataset Information

An imprinted gene network that controls mammalian somatic growth is down-regulated during postnatal growth deceleration in multiple organs.

Publications

An imprinted gene network that controls mammalian somatic growth is down-regulated during postnatal growth deceleration in multiple organs.

Similar Datasets

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