Signaling And Transcription Regulation In Nervous System

神经系统中的信号传导和转录调节

• 批准号: 6501277
• 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/6501277
• 关键词: biological signal transduction; cell differentiation; cell proliferation; central nervous system; developmental genetics; developmental neurobiology; fibroblast growth factor; gene expression; gene mutation; genetic regulation; genetically modified animals; growth factor receptors; laboratory mouse; labyrinth; neural crest; neurogenesis; phosphorylation; posttranslational modifications; protein structure; regulatory gene; retina; retinal pigment epithelium; sensorineural hearing loss; transcription factor; vesicle /vacuole

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. The neuroepithelial pigment cells are crucial for the development and function of the eye, and the neural crest-derived pigment cells for the development and function of the inner ear. Both types of pigment cells depend on the basic helix-loop-helix-zipper transcription factor MITF that regulates their proliferation and the expression of several pigment cell-specific genes. In the optic vesicle, MITF is initially 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. In situations where this downregulation does not occur, either experimentally or as a result of mutations in distinct MITF-regulatory genes, retinal cell proliferation is impeded or even abrogated at the expense of development into pigment cells. This highlights the role of extracellular signaling and the importance of MITF in regulating cell proliferation and differentiation. In the neural crest, where the tyrosine kinase receptor KIT and the G-coupled receptor EDNRB play key roles in pigment cell development, signaling through these receptors does not appear to regulate Mitf expression transcriptionally but may rather modulate MITF by post-translational modifications. Using phospho-MITF-specific antibodies and phosphorylation site-specific mutational approaches in mice, we are currently focusing on the elucidation of the underlying molecular principles of these regulations. Furthermore, by studying MITF in invertebrates and early vertebrates, we are correlating the organization and function(s) of Mitf 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，我们专注于从两个来源中的两种来源（神经rest或神经上皮的神经上皮）中得出的色素细胞的发展。神经上皮色素细胞对于眼睛的发育和功能至关重要，而神经rest衍生的色素细胞对于内耳的发育和功能至关重要。两种类型的色素细胞都取决于基本的螺旋 - 环螺旋转录因子MITF，该因子调节其增殖和几种色素细胞特异性基因的表达。在视线囊泡中，MITF最初与视网膜转录因子共表达。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刺激的信号，然后在推定的视网膜中转录下调MITF。在没有发生这种下调的情况下，无论是在实验中还是由于不同MITF调节基因的突变，视网膜细胞增殖都会阻碍或什至废除，以发展为色素细胞的发育。这突出了细胞外信号传导的作用以及MITF在调节细胞增殖和分化中的重要性。在神经rest中，酪氨酸激酶受体试剂盒和G偶联受体EDNRB在色素细胞发育中起关键作用，通过这些受体的信号传导似乎并未在转录上调节MITF表达，但可能会通过后翻译后修饰调节MITF。使用小鼠中的磷酸-MITF特异性抗体和磷酸化位点特异性突变方法，我们目前着重于阐明这些法规的基本分子原理。此外，通过研究无脊椎动物和早期脊椎动物中的MITF，我们将MITF的组织和功能与神经上皮和神经crest的独特进化史相关联。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。