title: Neurofibromin regulates somatic growth through the hypothalamic-pituitary axis.
abstract: To study the role of the neurofibromatosis-1 (NF1) gene in mammalian brain development, we recently generated mice in which Nf1 gene inactivation occurs in neuroglial progenitor cells using the brain lipid binding protein (BLBP) promoter. We found that Nf1(BLBP)CKO mice exhibit significantly reduced body weights and anterior pituitary gland sizes. We further demonstrate that the small anterior pituitary size reflects loss of neurofibromin expression in the hypothalamus, leading to reduced growth hormone releasing hormone, pituitary growth hormone (GH) and liver insulin-like growth factor-1 (IGF1) production. Since neurofibromin both negatively regulates Ras activity and positively modulates cAMP levels, we examined the signaling pathway responsible for these abnormalities. While BLBP-mediated expression of an activated Ras molecule did not recapitulate the body weight and hypothalamic/pituitary defects, treatment of Nf1(BLBP)CKO mice with rolipram to increase cAMP levels resulted in a partial restoration of the body weight phenotype. Furthermore, conditional expression of the Ras regulatory GAP domain of neurofibromin also did not rescue the body weight or Igf1 mRNA defects in Nf1(BLBP)CKO mice. Collectively, these data demonstrate a critical role for neurofibromin in hypothalamic-pituitary axis function and provide further insights into the short stature and GH deficits seen in children with NF1.
authors.affiliation: Department of Neurology, Washington University School of Medicine, St Louis, MO 63110, USA.
authors.forename: Balazs
authors.initials: B
authors.lastname: Hegedus
authors.forename: Tu-Hsueh
authors.initials: TH
authors.lastname: Yeh
authors.forename: Da Yong
authors.initials: DY
authors.lastname: Lee
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Emnett
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.forename: David H
authors.initials: DH
authors.lastname: Gutmann
mesh_terms: D000818:Animals; D001835:Body Weight; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D013006:Growth Hormone / Q000378:metabolism; D006801:Humans; D007018:Hypopituitarism / Q000235:genetics / Q000378:metabolism; D007031:Hypothalamus / Q000737:chemistry / Q000254:growth & development* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009456:Neurofibromatosis 1 / Q000235:genetics / Q000378:metabolism*; D025542:Neurofibromin 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009929:Organ Size; D010902:Pituitary Gland / Q000737:chemistry / Q000254:growth & development* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D015398:Signal Transduction
chemical_list: C086936:Fabp7 protein, mouse; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D009419:Nerve Tissue Proteins; D025542:Neurofibromin 1; D013006:Growth Hormone