Regulation Of Brain And Reproductive System Development

Child Health And Human Development

Investigators

Linked publications & trials

Abstract

IGF-I and Brain Development We have previously shown that insulin like growth factor 1 (IGF1) plays an important role in brain maturation by augmenting neuronal metabolism . Signal pathways similar to those used by insulin in the periphery are activated by IGF1 in the brain to stimulate glucose uptake, phosphorylation and incorporation into glycogen. We have recently shown that survival of dentate gyrus neurons is selectively impaired and that the dendritic growth of cortical neurons is dramatically reduced in the brains of Igf1 knockout mice. These findings help to explain the etiology of mental retardation in individuals with genetic defects in IGF1 synthesis. Current work is aimed at elucidating the factors regulating brain IGF1 expression during development, with certain fatty acids emerging as important players. Testosterone protects the mammary gland In our study of menopausal hormone replacement, we have found that addition of physiological androgen replacement significantly inhibits estrogen induced mammary epithelial proliferation, suggesting that combined estrogen/androgen treatment may attenuate or prevent the estrogen-induced increase in breast cancer. We have shown these protective androgenic effects are associated with testosterone's down-regulation of ER-alpha and up-regulation of ER-beta. Since ER-alpha is responsible for estrogen's mitogenic effects and induction of the oncogene c-myc, this reversal in ER-alpha/beta ratio may explain testosterone's anti-mitogenic effects. In support of this view, we have also shown that c-myc expression is significantly reduced in the mammary epithelium of the estrogen plus testosterone group. Turner Syndrome Turner Syndrome (TS) involves the loss of all or part of one sex chromosome, and affects 1/2500 live female births. We have recently initiated genotype-phenotype studies aimed at identifying X-chromosome genes responsible for abnormalities in development and function of brain, cardiovascular system and ovary in TS. There is an additional focus in these new studies on the clinical characterization and genetic tracking of metabolic disorders, including osteoporosis, glucose intolerance, hypertension and dyslipidemia, that appear to affect greater than expected numbers of individuals with TS. Several studies have reported an increased prevalence of bone fractures in TS, which has been attributed either to SHOX deletion or to estrogen insufficiency due to ovarian failure. We have shown that when fracture history is carefully documented through personal interviews with both subjects and age-matched controls, there is no excess of fractures in TS. Moreover, we have demonstrated that bone mineral density- when measured using volumetric methods not dependent on bone size- is virtually normal in TS women on conventional hormone replacement treatment. This analysis appears to exclude a role for the SHOX gene product in preventing osteoporosis or bone fragility. Reports on diabetes mellitus (DM) in TS have varied widely, with some studies indicating prevalence up to 40% and others finding no increase over normal populations (~5%). We have now shown that while most girls and women with TS have normal fasting glucose and insulin, the response to a glucose challenge is dramatically abnormal in at least 40%, and this is found in lean young women, after exclusion of obese subjects from the analysis. Multivariate analyses have also excluded significant contributions of family history and ovarian failure to this diabetic phenotype. Preliminary data suggest a primary insulin secretory defect in young lean women and girls with TS, without evidence of insulin resistance as seen in typical type 2 DM. Since ~40% of the group are affected, and the same proportion gets their single normal X from the father, we hypothesize that a gene promoting pancreatic insulin synthesis/secretion is selectively active on the maternal X but imprinted or silent on the paternal X-chromosome. Genotyping of parental chromosomes will allow testing of this hypothesis, and evaluation of subjects with partial X deletions will allow us to search for specific gene(s) responsible for this metabolic phenotype.