Neurofibromin regulates somatic growth through the hypothalamic-pituitary axis

Balazs Hegedus, Tu Hsueh Yeh, Da Yong Lee, Ryan J. Emnett, Jia Je Li, David H. Gutmann

研究成果: 雜誌貢獻文章同行評審

34 引文 斯高帕斯(Scopus)

摘要

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 Nf1BLBPCKO 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 Nf1BLBPCKO 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 Nf1BLBPCKO 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.
原文英語
頁(從 - 到)2956-2966
頁數11
期刊Human Molecular Genetics
17
發行號19
DOIs
出版狀態已發佈 - 2008
對外發佈

ASJC Scopus subject areas

  • 分子生物學
  • 遺傳學
  • 遺傳學(臨床)

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