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Human Molecular Genetics Advance Access originally published online on July 9, 2008
Human Molecular Genetics 2008 17(19):2956-2966; doi:10.1093/hmg/ddn194
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Neurofibromin regulates somatic growth through the hypothalamic–pituitary axis

Balazs Hegedus1, Tu-Hsueh Yeh1,2, Da Yong Lee1, Ryan J. Emnett1, Jia Li1 and David H. Gutmann1,*

1 Department of Neurology, Washington University School of Medicine, St Louis, MO 63110, USA 2 Department of Neurology, Chang Gung Memorial Hospital and University, Taipei, Taiwan, Republic of China

* To whom correspondence should be addressed at: Department of Neurology, Washington University School of Medicine, PO Box 8111, 660 South Euclid Avenue, St Louis, MO 63110, USA. Email: gutmannd{at}neuro.wustl.edu

Received March 17, 2008; Revised May 21, 2008; Accepted July 3, 2008

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.


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