Angelastro James M, Mason Jeffrey L, Ignatova Tatyana N, Kukekov Valery G, Stengren George B, Goldman James E, Greene Lloyd A
Department of Pathology and Center for Neurobiology and Behavior, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
J Neurosci. 2005 Apr 13;25(15):3889-99. doi: 10.1523/JNEUROSCI.3447-04.2005.
The mechanisms that regulate neural progenitor cell differentiation are primarily unknown. The transcription factor activating transcription factor 5 (ATF5) is expressed in neural progenitors of developing brain but is absent from mature astrocytes and neurons. Here, we demonstrate that ATF5 regulates the conversion of ventricular zone (VZ) and subventricular zone (SVZ) neural progenitors into astrocytes. Constitutive ATF5 expression maintains neural progenitor cell proliferation and blocks their in vitro and in vivo differentiation into astrocytes. Conversely, loss of ATF5 function promotes cell-cycle exit and allows astrocytic differentiation in vitro and in vivo. CNTF, a promoter of astrocytic differentiation, downregulates endogenous ATF5, whereas constitutively expressed ATF5 suppresses CNTF-promoted astrocyte genesis. Unexpectedly, constitutive ATF5 expression in neonatal SVZ cells both in vitro and in vivo causes them to acquire properties and anatomic distributions of VZ cells. These findings identify ATF5 as a key regulator of astrocyte formation and potentially of the VZ to SVZ transition.
调节神经祖细胞分化的机制目前主要尚不明确。转录因子激活转录因子5（ATF5）在发育中大脑的神经祖细胞中表达，但在成熟星形胶质细胞和神经元中不存在。在此，我们证明ATF5调节脑室区（VZ）和脑室下区（SVZ）神经祖细胞向星形胶质细胞的转化。组成型ATF5表达维持神经祖细胞增殖，并阻断其在体外和体内向星形胶质细胞的分化。相反，ATF5功能丧失促进细胞周期退出，并允许在体外和体内进行星形胶质细胞分化。CNTF是星形胶质细胞分化的促进因子，可下调内源性ATF5，而组成型表达的ATF5则抑制CNTF促进的星形胶质细胞生成。出乎意料的是，在体外和体内新生SVZ细胞中组成型ATF5表达使它们获得VZ细胞的特性和解剖分布。这些发现确定ATF5是星形胶质细胞形成以及潜在的从VZ到SVZ转变的关键调节因子。
