Huang Siyi, O'Donovan Kevin J, Turner Eric E, Zhong Jian, Ginty David D
Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, United States.
Department of Neuroscience, Howard Hughes Medical Institute, Johns Hopkins School of Medicine, Baltimore, United States.
Elife. 2015 Sep 29;4:e10874. doi: 10.7554/eLife.10874.
The generation of diverse neuronal subtypes involves specification of neural progenitors and, subsequently, postmitotic neuronal differentiation, a relatively poorly understood process. Here, we describe a mechanism whereby the neurotrophic factor NGF and the transcription factor Runx1 coordinate postmitotic differentiation of nonpeptidergic nociceptors, a major nociceptor subtype. We show that the integrity of a Runx1/CBFβ holocomplex is crucial for NGF-dependent nonpeptidergic nociceptor maturation. NGF signals through the ERK/MAPK pathway to promote expression of Cbfb but not Runx1 prior to maturation of nonpeptidergic nociceptors. In contrast, transcriptional initiation of Runx1 in nonpeptidergic nociceptor precursors is dependent on the homeodomain transcription factor Islet1, which is largely dispensable for Cbfb expression. Thus, an NGF/TrkA-MAPK-CBFβ pathway converges with Islet1-Runx1 signaling to promote Runx1/CBFβ holocomplex formation and nonpeptidergic nociceptor maturation. Convergence of extrinsic and intrinsic signals to control heterodimeric transcription factor complex formation provides a robust mechanism for postmitotic neuronal subtype specification.
多种神经元亚型的产生涉及神经祖细胞的特化，以及随后有丝分裂后神经元的分化，这是一个相对了解较少的过程。在这里，我们描述了一种机制，通过该机制神经营养因子NGF和转录因子Runx1协调非肽能伤害感受器（一种主要的伤害感受器亚型）的有丝分裂后分化。我们表明，Runx1/CBFβ全复合物的完整性对于NGF依赖的非肽能伤害感受器成熟至关重要。在非肽能伤害感受器成熟之前，NGF通过ERK/MAPK途径发出信号，以促进Cbfb而非Runx1的表达。相反，非肽能伤害感受器前体中Runx1的转录起始依赖于同源结构域转录因子Islet1，而Islet1对于Cbfb表达在很大程度上是可有可无的。因此，NGF/TrkA-MAPK-CBFβ途径与Islet1-Runx1信号传导汇聚，以促进Runx1/CBFβ全复合物的形成和非肽能伤害感受器的成熟。外在和内在信号的汇聚以控制异二聚体转录因子复合物的形成，为有丝分裂后神经元亚型的特化提供了一种强大的机制。
