美國(guó)華盛頓大學(xué)醫(yī)學(xué)院研究人員發(fā)現(xiàn),，神經(jīng)纖維瘤1型（neurofibromatosis 1）基因NF1是腦早期發(fā)育的關(guān)鍵基因,。NF1通過(guò)c-AMP依賴和Ras依賴的兩種信號(hào)機(jī)制，調(diào)節(jié)神經(jīng)角質(zhì)前體細(xì)胞（neuroglial progenitor）分別分化為神經(jīng)元和神經(jīng)角質(zhì)細(xì)胞,。相關(guān)結(jié)果發(fā)表在10月11日Cell Stem Cell上。
美國(guó)有10萬(wàn)多名患有神經(jīng)纖維瘤1型疾病的患者,。15%-20%患者的腦瘤來(lái)自于星形角質(zhì)細(xì)胞的突變,，而60%-70%患者中認(rèn)知性障礙則由于神經(jīng)元病變。
兩種癥狀隨機(jī)或同時(shí)發(fā)生的現(xiàn)象,，使得科學(xué)家迷惑不解——因?yàn)閱蝹€(gè)基因的突變影響到兩種不同的細(xì)胞表型,。神經(jīng)膠質(zhì)細(xì)胞主要提供支持，保護(hù)和滋潤(rùn)神經(jīng)元的作用,，而神經(jīng)元?jiǎng)t通過(guò)相互交流處理思維和記憶,。
研究人員培育出一種小鼠系,，這種小鼠可選擇性關(guān)閉其體內(nèi)神經(jīng)干細(xì)胞中與人類NF-1相對(duì)應(yīng)的基因。研究發(fā)現(xiàn),，NF1表達(dá)蛋白神經(jīng)纖維瘤素Nf1參與兩條信號(hào)傳導(dǎo)途徑,，即c-AMP依賴途徑和Ras依賴途徑，從而使得神經(jīng)纖維瘤素可調(diào)控兩種細(xì)胞的發(fā)育,。通過(guò)Ras依賴途徑對(duì)星形膠質(zhì)細(xì)胞的發(fā)育必不可少,，但對(duì)神經(jīng)元細(xì)胞的發(fā)育則并不必須。反過(guò)來(lái),，c-AMP依賴途徑則對(duì)神經(jīng)元細(xì)胞的發(fā)育至關(guān)重要,。
研究人員提示，對(duì)神經(jīng)纖維瘤的治療可以通過(guò)雙重途徑展開(kāi),。同時(shí),，因?yàn)樵诮馄蕦W(xué)上，神經(jīng)纖維瘤1型病人腦部并沒(méi)有非常明顯的結(jié)構(gòu)缺陷,，對(duì)該Nf1小鼠系的研究將提供相關(guān)問(wèn)題所在,，從而可以更好理解與認(rèn)知障礙關(guān)聯(lián)的神經(jīng)纖維瘤1型疾病。（生命科學(xué)專輯）
王小理 編譯自 http://www.eurekalert.org/pub_releases/2007-11/wuis-cgd111307.php
原始出處:
Cell Stem Cell, Vol 1, 443-457, 11 October 2007
Article
Neurofibromatosis-1 Regulates Neuronal and Glial Cell Differentiation from Neuroglial Progenitors In Vivo by Both cAMP- and Ras-Dependent Mechanisms
Balazs Hegedus,1 Biplab Dasgupta,1,3 Jung Eun Shin,1 Ryan J. Emnett,1 Elizabeth K. Hart-Mahon,1 Lynda Elghazi,2 Ernesto Bernal-Mizrachi,2 and David H. Gutmann1,
1 Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA
2 Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
Corresponding author
David H. Gutmann
[email protected]
Individuals with neurofibromatosis type 1 (NF1) develop abnormalities of both neuronal and glial cell lineages, suggesting that the NF1 protein neurofibromin is an essential regulator of neuroglial progenitor function. In this regard, Nf1-deficient embryonic telencephalic neurospheres exhibit increased self-renewal and prolonged survival as explants in vivo. Using a newly developed brain lipid binding protein (BLBP)-Cre mouse strain to study the role of neurofibromin in neural progenitor cell function in the intact animal, we now show that neuroglial progenitor Nf1 inactivation results in increased glial lineage proliferation and abnormal neuronal differentiation in vivo. Whereas the glial cell lineage abnormalities are recapitulated by activated Ras or Akt expression in vivo, the neuronal abnormalities were Ras- and Akt independent and reflected impaired cAMP generation in Nf1-deficient cells in vivo and in vitro. Together, these findings demonstrate that neurofibromin is required for normal glial and neuronal development involving separable Ras-dependent and cAMP-dependent mechanisms.
