Neurofibromin regulates somatic growth through the hypothalamic-pituitary axis.
Neurofibromin regulates somatic growth through the hypothalamic-pituitary axis.
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DOI：
10.1093/hmg/ddn194
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发表时间：
2008-10-01
影响因子：
3.5
通讯作者：
Gutmann DH
中科院分区：
文献类型：
--
作者：
Hegedus B;Yeh TH;Lee DY;Emnett RJ;Li J;Gutmann DH
为了研究神经纤维瘤病-1（NF 1）基因在哺乳动物脑发育中的作用，我们最近产生了小鼠，其中NF 1基因失活发生在神经胶质祖细胞中使用脑脂质结合蛋白（BLBP）启动子。我们发现，Nf 1BLBPCKO小鼠表现出显着降低体重和垂体前叶大小。我们进一步证明，小垂体前叶大小反映了神经纤维蛋白在下丘脑表达的损失，导致生长激素释放激素，垂体生长激素（GH）和肝脏胰岛素样生长因子-1（IGF 1）的生产减少。由于神经纤维蛋白既负调节Ras活性，又正调节cAMP水平，我们研究了导致这些异常的信号通路。虽然BLBP介导的活化Ras分子的表达并不能重现体重和下丘脑/垂体缺陷，但用咯利普兰治疗Nf 1BLBPCKO小鼠以增加cAMP水平导致体重表型的部分恢复。此外，神经纤维蛋白的Ras调节GAP结构域的条件表达也不能挽救Nf 1BLBPCKO小鼠的体重或Igf 1 mRNA缺陷。总的来说，这些数据证明了神经纤维蛋白在下丘脑-垂体轴功能中的关键作用，并提供了对NF 1儿童中观察到的身材矮小和GH缺陷的进一步了解。
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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影响因子：
25
作者：
Arumugam, H;Liu, XH;Belousov, AB
通讯作者：
Belousov, AB
影响因子：
4
作者：
Bartholdi, Deborah;Roelfsema, Jeroen H.;Peters, Dorien J. M.
通讯作者：
Peters, Dorien J. M.
影响因子：
4.8
作者：
CUGINI, CD;MILLARD, WJ;LEIDY, JW
通讯作者：
LEIDY, JW
影响因子：
3.5
作者：
Hannan, F;Ho, I;Zhong, Y
通讯作者：
Zhong, Y
影响因子：
4.8
作者：
LEE, D;HUANG, WQ;LIM, AT
通讯作者：
LIM, AT