Shalizi Aryaman, Lehtinen Maria, Gaudilliere Brice, Donovan Nicole, Han Jiahuai, Konishi Yoshiyuki, Bonni Azad
Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.
J Neurosci. 2003 Aug 13;23(19):7326-36. doi: 10.1523/JNEUROSCI.23-19-07326.2003.
The temporally specific nature of neurotrophic factor-induced responses is a general feature of mammalian nervous system development, the mechanisms of which remain to be elucidated. We characterized a mechanism underlying the temporal specificity by which BDNF selectively promotes the survival of newly generated, but not mature, granule neurons of the mammalian cerebellum. We found that BDNF specifically induces the extracellular signal-regulated kinase 5 (ERK5)-myocyte enhancer factor (MEF2) signaling pathway in newly generated granule neurons and thereby induces transcription of neurotrophin-3 (NT-3), a novel gene target of MEF2. Inhibition of endogenous ERK5, MEF2, or NT-3 in neurons by several approaches including disruption of the NT-3 gene in mice revealed a requirement for the ERK5-MEF2-NT-3 signaling pathway in BDNF-induced survival of newly generated granule neurons. These findings define a novel mechanism that underlies the antiapoptotic effect of neurotrophins in a temporally defined pattern in the developing mammalian brain.
神经营养因子诱导反应的时间特异性是哺乳动物神经系统发育的一个普遍特征，其机制仍有待阐明。我们描述了一种时间特异性的潜在机制，通过该机制，脑源性神经营因子（BDNF）选择性地促进哺乳动物小脑新生成而非成熟的颗粒神经元的存活。我们发现，BDNF在新生成的颗粒神经元中特异性地诱导细胞外信号调节激酶5（ERK5）-肌细胞增强因子（MEF2）信号通路，从而诱导神经营养因子3（NT-3）的转录，NT-3是MEF2的一个新的基因靶点。通过包括破坏小鼠NT-3基因在内的几种方法抑制神经元中的内源性ERK5、MEF2或NT-3，揭示了ERK5-MEF2-NT-3信号通路对BDNF诱导的新生成颗粒神经元存活的必要性。这些发现定义了一种新机制，该机制是神经营养因子在发育中的哺乳动物大脑中以时间限定模式发挥抗凋亡作用的基础。
