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An Extensive Genetic Program Occurring during Postnatal Growth in Multiple Tissues

Developmental Endocrinology Branch (G.P.F., P.F., J.C.K.L., K.M.B., R.M., S.M., V.N., J.E.L., O.N., J.B.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; and Center for Molecular Medicine and Pediatric Endocrinology Unit (O.N.), Department of Woman and Child Health, Karolinska Institutet and Karolinska University Hospital, SE-171 76 Stockholm, Sweden

Address all correspondence and requests for reprints to: Jeffrey Baron, M.D., Developmental Endocrinology Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, CRC, Room 1-3330, 10 Center Drive, MSC-1103, Bethesda, Maryland 20892-1103. E-mail: jeffrey.baron{at}nih.gov.

Mammalian somatic growth is rapid in early postnatal life but then slows and eventually ceases in multiple tissues. We hypothesized that there exists a postnatal gene expression program that is common to multiple tissues and is responsible for this coordinate growth deceleration. Consistent with this hypothesis, microarray analysis identified more than 1600 genes that were regulated with age (1 vs. 4 wk) coordinately in kidney, lung, and heart of male mice, including many genes that regulate proliferation. As examples, we focused on three growth-promoting genes, Igf2, Mest, and Peg3, that were markedly down-regulated with age. In situ hybridization revealed that expression occurred in organ-specific parenchymal cells and suggested that the decreasing expression with age was due primarily to decreased expression per cell rather than a decreased number of expressing cells. The declining expression of these genes was slowed during hypothyroidism and growth inhibition (induced by propylthiouracil at 0–5 wk of age) in male rats, suggesting that the normal decline in expression is driven by growth rather than by age per se. We conclude that there exists an extensive genetic program occurring during postnatal life. Many of the involved genes are regulated coordinately in multiple organs, including many genes that regulate cell proliferation. At least some of these are themselves apparently regulated by growth, suggesting that, in the embryo, a gene expression pattern is established that allows for rapid somatic growth of multiple tissues, but then, during postnatal life, this growth leads to negative-feedback changes in gene expression that in turn slow and eventually halt somatic growth, thus imposing a fundamental limit on adult body size.