GABAergic Differentiation Induced by Mash1 Is Compromised by the bHLH Proteins Neurogenin2, NeuroD1, and NeuroD2

被引:55
作者
Roybon, Laurent [2 ]
Mastracci, Teresa L. [1 ]
Ribeiro, Diogo [2 ]
Sussel, Lori [1 ]
Brundin, Patrik [2 ]
Li, Jia-Yi [2 ]
机构
[1] Columbia Univ, Coll Phys & Surg, Dept Genet & Dev, New York, NY 10032 USA
[2] Wallenberg Neurosci Ctr, Dept Expt Med Sci, Neuronal Survival Unit, S-22184 Lund, Sweden
基金
瑞典研究理事会;
关键词
fate; GABAergic; identity; LGE; Mash1; neural progenitor; NeuroD1; NeuroD2; Neurogenin2; NEURAL STEM-CELLS; TRANSCRIPTION FACTORS; DIRECTED DIFFERENTIATION; HIPPOCAMPAL NEUROGENESIS; DETERMINATION GENES; PROGENITOR CELLS; NGN2; EXPRESSION; IDENTITY; SPECIFICATION;
D O I
10.1093/cercor/bhp187
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
During forebrain development, Mash1 directs gamma-aminobutyric acid (GABA)ergic neuron differentiation ventrally in the ganglionic eminences. Repression of Mash1 in the cortex is necessary to prevent the formation of GABAergic interneurons. Negative regulation of Mash1 has been attributed to members of the Neurogenin family; the genetic ablation of Neurogenin2 (Ngn2) leads to the derepression of Mash1 and the formation of ectopic GABAergic neurons in the cortex. We have developed an in vitro system to clarify the importance of NeuroD proteins in the Mash1 regulatory pathway. Using a neurosphere culture system, we show that the downstream effectors of the Ngn2 pathway NeuroD1 and NeuroD2 can abrogate GABAergic differentiation directed by Mash1. The ectopic expression of either of these genes in Mash1-expressing cells derived from the lateral ganglionic eminence, independently downregulate Mash1 expression without affecting expression of distal less homeodomain genes. This results in a complete loss of the GABAergic phenotype. Moreover, we demonstrate that ectopic expression of Mash1 in cortical progenitors is sufficient to phenocopy the loss of Ngn2 and strongly enhances ectopic GABAergic differentiation. Collectively, our results define the compensatory and cross-regulatory mechanisms that exist among basic helix-loop-helix transcription factors during neuronal fate specification.
引用
收藏
页码:1234 / 1244
页数:11
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