Evolutionary conservation and modulation of a juvenile growth-regulating genetic program

  1. Julian C K Lui1*
  1. 1Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development
    2Microarray Core Facility, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 10 Center Drive, MSC-1103; Building 10, Room 1-3330, Bethesda, Maryland 20892, USA
    3Department of Pediatrics and the Reproductive Sciences Program, The University of Michigan, Ann Arbor, Michigan, USA
  1. Correspondence should be addressed to J Baron; Email: jeffrey.baron{at}nih.gov
  1. Figure 1

    A multiorgan growth-regulating genetic program common to mice, rats, and sheep. (A) Venn diagrams showing the number of genes significantly downregulated and upregulated with age by microarray in sheep vs mouse and rat. Genes that showed significant age regulation (FDR<0.1) in both kidney and lung in sheep were compared with the 174 genes downregulated or the 58 genes upregulated in all organs studied in mouse and rat. *P<0.001. (B) Gene ontology analysis of the genes that were age-regulated in both organs in sheep (FDR<0.1). Downregulated (886) and upregulated (798) genes were analysed separately using Ingenuity Pathway Analysis. Only cellular and molecular functions with P<0.005 after Benjamini–Hochberg correction are listed. (C) Heat map based on microarray analysis of the 232 genes that were commonly down- or upregulated with age in the mouse (columns 1–4) and rat (columns 5–6) and present in the sheep microarray (columns 7–10). Each row corresponds to a gene, ranked by average fold change in mouse and rat. (D) Heat map similar to (C) but excluding 78 genes that have a known function specific to the cell cycle. Green, downregulation with age; red, upregulation. Scale values are log2 (fold difference). P, postnatal age (weeks); F, fetal age (days); AD, adult (21 months).

  2. Figure 2

    Rate of decline in growth velocity varies among mouse, rat, and sheep. Percent change in body weight per change in time was calculated for mouse (dotted line) based on weights at 4, 7, 9, 12, 15, and 19 weeks postfertilization; rat (dashed line) at 6, 7, 9, 12, and 15 weeks postfertilization; and sheep (solid line) at 9, 13, 24, 31, 42, and 111 weeks postfertilization. Age is expressed as weeks postfertilization to account for interspecies differences in gestational age.

  3. Figure 3

    The pace of the multiorgan juvenile genetic program differs among species of different body size. (A) Mice vs rats. For the 235 genes that were downregulated with age in all organs studied in mouse and rat, we compared the fold change in expression from 1 to 4 weeks of age in the mouse vs 1 to 5 weeks in the rat by microarray. Negative values indicate decreasing expression. Boundaries of the box, 25th and 75th percentile; bars, 10th and 90th percentiles; central line segment, median. (B) Mice vs sheep. For genes that were commonly downregulated in all organs studied of all three species, we compared the expression patterns in mice and sheep by microarray. Age is expressed as weeks postfertilization to account for differences in the length of gestation. Relative expression was normalized to the young adult time point in each species (mouse, 11 weeks; sheep, 111 weeks). Dotted line separates data from different microarray experiments.

  4. Figure 4

    Downregulation of specific growth-regulating genes occurs more slowly in sheep (open circles) than in mice (closed circles). mRNA relative expression (mean±s.e.m.) was assessed by quantitative RT-PCR. Top to bottom row: kidney, lung, heart, and liver. Relative expression was normalized to the young adult time point in each species (mouse, 11 weeks; sheep, 111 weeks).

| Table of Contents