Bertrand Vincent, Hobert Oliver
Department of Biochemistry and Molecular Biophysics, Howard Hughes Medical Institute, Columbia University Medical Center, New York, NY 10032, USA.
Dev Cell. 2009 Apr;16(4):563-75. doi: 10.1016/j.devcel.2009.02.011.
How asymmetric divisions are connected to the terminal differentiation program of neuronal subtypes is poorly understood. In C. elegans, two homeodomain transcription factors, TTX-3 (a LHX2/9 ortholog) and CEH-10 (a CHX10 ortholog), directly activate a large battery of terminal differentiation genes in the cholinergic interneuron AIY. We establish here a transcriptional cascade linking asymmetric division to this differentiation program. A transient lineage-specific input formed by the Zic factor REF-2 and the bHLH factor HLH-2 directly activates ttx-3 expression in the AIY mother. During the terminal division of the AIY mother, an asymmetric Wnt/beta-catenin pathway cooperates with TTX-3 to directly restrict ceh-10 expression to only one of the two daughter cells. TTX-3 and CEH-10 automaintain their expression, thereby locking in the differentiation state. Our study establishes how transient lineage and asymmetric division inputs are integrated and suggests that the Wnt/beta-catenin pathway is widely used to control the identity of neuronal lineages.
不对称分裂如何与神经元亚型的终末分化程序相关联，目前仍知之甚少。在秀丽隐杆线虫中，两个同源结构域转录因子TTX-3（LHX2/9直系同源物）和CEH-10（CHX10直系同源物）直接激活胆碱能中间神经元AIY中的大量终末分化基因。我们在此建立了一个将不对称分裂与该分化程序联系起来的转录级联。由锌指因子REF-2和bHLH因子HLH-2形成的短暂的谱系特异性输入直接激活AIY母细胞中的ttx-3表达。在AIY母细胞的终末分裂过程中，不对称的Wnt/β-连环蛋白信号通路与TTX-3协同作用，将ceh-10的表达直接限制在两个子细胞中的一个。TTX-3和CEH-10自动维持它们的表达，从而锁定分化状态。我们的研究确定了短暂的谱系和不对称分裂输入是如何整合的，并表明Wnt/β-连环蛋白信号通路被广泛用于控制神经元谱系的特性。
