A nonclassical bHLH-Rbpj transcription factor complex is required for specification of GABAergic neurons independent of Notch signaling
A nonclassical bHLH-Rbpj transcription factor complex is required for specification of GABAergic neurons independent of Notch signaling
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DOI：
10.1101/gad.1628008
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发表时间：
2008-01-15
影响因子：
10.5
通讯作者：
Johnson, Jane E.
中科院分区：
文献类型：
--
作者：
Hori, Kei;Cholewa-Waclaw, Justyna;Johnson, Jane E.
神经网络通过抑制性和兴奋性神经元活动来平衡。这些网络的形成最初是通过转录因子控制的神经元亚型规范产生的。碱性螺旋-环-螺旋 (bHLH) 转录因子 Ptf1a 对于背侧脊髓、小脑和视网膜中 GABA 能抑制性神经元的生成至关重要。转录因子 Rbpj 是 Notch 信号通路的转导因子，其功能是维持神经祖细胞。在这里，我们证明了 Ptf1a 和 Rbpj 在体内形成 GABA 能神经元规范所需的复合物中相互作用，这种功能不能被经典形式的 bHLH 异二聚体与 E 蛋白或通过 Rbpj 的 Notch 信号传导所取代。我们发现，无法结合 Rbpj 的 Ptf1a 突变体虽然保留了与 E 蛋白相互作用的能力，但无法在鸡和小鼠神经管中诱导 GABA 能 (Pax2) 表达细胞和抑制谷氨酸能 (Tlx3) 表达细胞。此外，我们使用 Rbpj 条件突变来证明 Rbpj 功能对于 GABAergic 规范至关重要，并且该功能独立于 Notch 信号通路。总之，这些发现证明了 Ptf1a - Rbpj 复合物在控制发育中的脊髓中抑制性和兴奋性神经元的平衡形成方面的需要，并指出了 Rbpj 在神经系统发育中的一种新的不依赖于 Notch 的功能。
Neural networks are balanced by inhibitory and excitatory neuronal activity. The formation of these networks is initially generated through neuronal subtype specification controlled by transcription factors. The basic helix-loop-helix (bHLH) transcription factor Ptf1a is essential for the generation of GABAergic inhibitory neurons in the dorsal spinal cord, cerebellum, and retina. The transcription factor Rbpj is a transducer of the Notch signaling pathway that functions to maintain neural progenitor cells. Here we demonstrate Ptf1a and Rbpj interact in a complex that is required in vivo for specification of the GABAergic neurons, a function that cannot be substituted by the classical form of the bHLH heterodimer with E-protein or Notch signaling through Rbpj. We show that a mutant form of Ptf1a without the ability to bind Rbpj, while retaining its ability to interact with E-protein, is incapable of inducing GABAergic (Pax2)- and suppressing glutamatergic (Tlx3)- expressing cells in the chick and mouse neural tube. Moreover, we use an Rbpj conditional mutation to demonstrate that Rbpj function is essential for GABAergic specification, and that this function is independent of the Notch signaling pathway. Together, these findings demonstrate the requirement for a Ptf1a - Rbpj complex in controlling the balanced formation of inhibitory and excitatory neurons in the developing spinal cord, and point to a novel Notch-independent function for Rbpj in nervous system development.