A screen for downstream effectors of Neurogenin2 in the embryonic neocortex
A screen for downstream effectors of Neurogenin2 in the embryonic neocortex
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DOI：
10.1016/j.ydbio.2004.06.013
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发表时间：
2004-09-15
影响因子：
2.7
通讯作者：
Schuurmans, C
中科院分区：
文献类型：
--
作者：
Mattar, P;Britz, O;Schuurmans, C
神经生成素 (Ngn) 1 和 Ngn2 编码在发育中的新皮质中表达的碱性螺旋-环-螺旋转录因子。与其他原神经基因一样，Ngns 参与神经命运和神经元身份的规范，但下游效应器仍不清楚。我们着手使用消减杂交筛选来鉴定皮层中的 Ngn2 效应子，并鉴定了在 Ngn2 和 Ngn1;Ngt2 突变体中被错误调节的几个区域表达基因。包括在生发区祖细胞（例如 Nlgn1、Unc5H4 和 Dcc）以及皮质板（例如 Bhlhb5 和 NFIB）和亚板（例如 Mef2c、srGAP3 和原钙粘蛋白 9）中的有丝分裂后神经元中下调的基因。进一步的分析表明，Ngn2 突变的亚板神经元被错误指定，丘脑皮质传入神经元（ITCA）通常以该层为目标，而不是不适当地投射到生发区。引人注目的是，编码排斥性引导信号的 EphA5 和 Sema3c 在 Ngn2 和 Ngn1;Ngn2 突变生发区中下调，为轴突靶向缺陷提供了可能的分子基础。因此，我们鉴定了 Ngn1 和 Ngn2 下游激活的分化级联的几个新组件，并为这些原神经基因控制的新发育过程提供了新的见解。对我们筛选中分离的基因的进一步分析应该为理解皮质生成的分子机制提供丰富的基础。 (C) 2004 Elsevier Inc. 保留所有权利。
Neurogenin (Ngn) 1 and Ngn2 encode basic-helix-loop-helix transcription factors expressed in the developing neocortex. Like other proneural genes, Ngns participate in the specification of neural fates and neuronal identities, but downstream effectors remain poorly defined. We set out to identify Ngn2 effectors in the cortex using a subtractive hybridization screen and identified several regionally expressed genes that were misregulated in Ngn2 and Ngn1;Ngt2 mutants. Included were genes down-regulated in germinal zone progenitors (e.g., Nlgn1, Unc5H4, and Dcc) and in postmitotic neurons in the cortical plate (e.g., Bhlhb5 and NFIB) and subplate (e.g., Mef2c, srGAP3, and protocadherin 9). Further analysis revealed that Ngn2 mutant subplate neurons were misspecified and that thalamocortical afferents ITCAs) that normally target this layer instead inappropriately projected towards the germinal zone. Strikingly, EphA5 and Sema3c, which encode repulsive guidance cues, were down-regulated in the Ngn2 and Ngn1;Ngn2 mutant germinal zones, providing a possible molecular basis for axonal targeting defects. Thus, we identified several new components of the differentiation cascade(s) activated downstream of Ngn1 and Ngn2 and provided novel insights into a new developmental process controlled by these proneural genes. Further analysis of the genes isolated in our screen should provide a fertile basis for understanding the molecular mechanisms underlying corticogenesis. (C) 2004 Elsevier Inc. All rights reserved.