SIGNALING AND TRANSCRIPTION REGULATION IN NERVOUS SYSTEM DEVELOPMENT

神经系统发育中的信号传导和转录调节

• 批准号: 6432904
• 负责人: HEINZ ARNHEITER
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6432904
• 关键词: cell differentiation; cell type; developmental genetics; gene expression; gene induction /repression; gene mutation; genetic regulation; genetically modified animals; laboratory mouse; melanocyte; neural crest; retina; transcription factor; transposon /insertion element

The development of distinct cell lineages from unspecified precursors is the result of complex interactions between cell-extrinsic cues and the crucial programs of gene expression. To study such interactions, we are focusing on the development of pigment cells which are derived from either of two sources, the neural crest or the neuroepithelium of the optic vesicle, and which are of crucial importance for the development and function of sensory organs such as the eye and the ear. Both neural crest and neuroepithelial pigment cells depend on the basic helix-loop-helix-zipper transcription factor MITF that regulates cell proliferation and the expression of several genes involved in pigment synthesis. The dependence of MITF on regulation by growth factors, however, is fundamentally different in the optic neuroepithelium and the neural crest. In the optic vesicle, MITF is intially co-expressed along with retinal transcription factors. By signaling through FGF receptors which are tyrosine kinase receptors stimulated by FGFs emanating from the surface ectoderm, MITF is then downregulated transcriptionally in the presumptive retina, thus allowing the formation of a retina at the expense of a pigment epithelium. In contrast, in the neural crest, where the tyrosine kinase receptor KIT plays a key role in pigment cell development, KIT signaling does not regulate MITF expression transcriptionally. Rather, it appears to have a role in modulating MITF post-transcriptionally and in influencing the expression of MITF target genes in a gene-selective way. We are currently focusing on the elucidation of the underlying molecular principles of these differences. Furthermore, by studying MITF expression and function in invertebrates and early vertebrates, we are tyring to correlate these differences with the distinct evolutionary history of the neuroepithelium and the neural crest. These studies should ultimately help us in regulating cell fates in a precise manner and provide means to therapeutically replace degenerating cells as they are encountered, for instance, during the course of retinal diseases.

来自未指定的前体的不同细胞谱系的发展是细胞 - 超支线索之间的复杂相互作用与基因表达的关键程序之间的复杂相互作用的结果。为了研究这种相互作用，我们关注的是从两个来源中的两种来源中得出的色素细胞的开发，即视囊的神经rest或神经上皮，对于诸如眼睛和耳朵等感觉器官的发展和功能至关重要。神经rest和神经上皮色素细胞都取决于调节细胞增殖的基本螺旋 - 环螺旋转录因子MITF，以及与色素合成有关的几个基因的表达。然而，MITF对生长因子调节的依赖性在视神经上皮和神经rest中根本不同。在视线囊泡中，MITF与视网膜转录因子一起显着表达。通过通过FGF受体发出信号，这些受体是酪氨酸激酶受体受到表面外胚层发出的FGF的刺激的信号，然后在推定的视网膜中转录下调MITF，从而允许以色素上皮的费用以视网膜形成视网膜。相比之下，在神经波峰中，酪氨酸激酶受体试剂盒在色素细胞发育中起关键作用，试剂盒信号传导不会转录MITF表达。相反，它似乎在转录后调节MITF和以基因选择性的方式影响MITF靶基因的表达方面起作用。我们目前正在关注这些差异的基本分子原理。此外，通过研究无脊椎动物和早期脊椎动物中MITF的表达和功能，我们正在提倡这些差异与神经上皮的独特进化史和神经rest的不同进化史相关联。这些研究最终应以精确的方式帮助我们调节细胞命运，并提供治疗方法，以替代视网膜疾病过程中遇到的退化细胞。