Department of Biosciences, P.O. Box 56, Viikinkaari 5, FIN00014-University of Helsinki , Helsinki , Finland.
Biol Open. 2013 Aug 9;2(10):990-7. doi: 10.1242/bio.20135041. eCollection 2013.
Midbrain- and hindbrain-derived GABAergic interneurons are critical for regulation of sleep, respiratory, sensory-motor and motivational processes, and they are implicated in human neurological disorders. However, the precise mechanisms that underlie generation of GABAergic neuron diversity in the midbrain-hindbrain region are poorly understood. Here, we show unique and overlapping requirements for the related bHLH proteins Tal1 and Tal2 in GABAergic neurogenesis in the midbrain. We show that Tal2 and Tal1 are specifically and sequentially activated during midbrain GABAergic neurogenesis. Similar to Gata2, a post-mitotic selector of the midbrain GABAergic neuron identity, Tal2 expression is activated very early during GABAergic neuron differentiation. Although the expression of Tal2 and Gata2 genes are independent of each other, Tal2 is important for normal midbrain GABAergic neurogenesis, possibly as a partner of Gata2. In the absence of Tal2, the majority of midbrain GABAergic neurons switch to a glutamatergic-like phenotype. In contrast, Tal1 expression is activated in a Gata2 and Tal2 dependent fashion in the more mature midbrain GABAergic neuron precursors, but Tal1 alone is not required for GABAergic neuron differentiation from the midbrain neuroepithelium. However, inactivation of both Tal2 and Tal1 in the developing midbrain suggests that the two factors co-operate to guide GABAergic neuron differentiation in a specific ventro-lateral midbrain domain. The observed similarities and differences between Tal1/Tal2 and Gata2 mutants suggest both co-operative and unique roles for these factors in determination of midbrain GABAergic neuron identities.
中脑和后脑衍生的 GABA 能中间神经元对于调节睡眠、呼吸、感觉运动和动机过程至关重要，它们与人类神经紊乱有关。然而，中脑-后脑区域 GABA 能神经元多样性产生的精确机制还知之甚少。在这里，我们显示了相关 bHLH 蛋白 Tal1 和 Tal2 在中脑 GABA 能神经元发生中的独特和重叠的要求。我们表明 Tal2 和 Tal1 在中脑 GABA 能神经元发生中特异性和顺序激活。与 Gata2 相似，Gata2 是中脑 GABA 能神经元身份的一个有丝分裂后选择物，Tal2 的表达在 GABA 能神经元分化的早期就被激活。尽管 Tal2 和 Gata2 基因的表达彼此独立，但 Tal2 对正常中脑 GABA 能神经发生很重要，可能是 Gata2 的一个伴侣。在没有 Tal2 的情况下，大多数中脑 GABA 能神经元转变为谷氨酸能样表型。相比之下，在更成熟的中脑 GABA 能神经元前体中，Tal1 的表达以 Gata2 和 Tal2 依赖的方式被激活，但 Tal1 本身并不是从中脑神经上皮分化 GABA 能神经元所必需的。然而，在发育中的中脑中同时失活 Tal2 和 Tal1 表明这两个因素合作，在特定的腹外侧中脑区域指导 GABA 能神经元分化。Tal1/Tal2 和 Gata2 突变体之间观察到的相似性和差异表明这些因素在确定中脑 GABA 能神经元身份方面具有合作和独特的作用。
