权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Investigating the molecular mechanisms of early neuronal morphogenesis

研究早期神经元形态发生的分子机制

基本信息

批准号：
10545077
负责人：
Jernej Murn
金额：
$ 32.66万
依托单位：
UNIVERSITY OF CALIFORNIA RIVERSIDE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2027-01-01
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10545077
关键词：
Affect Binding Binding Sites Biochemical Biological Assay Bipolar Neuron Cell Shape Cell physiology Cells Cellular Morphology Code Coupled Cues Development Disease Dissociation Endowment Event FRAP1 gene Foundations Gene Expression Gene Structure Goals Homeostasis Individual Instruction Length Life Link Locales Mammalian Cell Mediating Messenger RNA Microscopy Modality Molecular Morphogenesis Morphology Mutagenesis Nature Neuroglia Neurons Organism Phosphorylation Phosphotransferases Play Poly(A) Tail Post-Transcriptional Regulation Post-Translational Protein Processing Process Proteins Proteomics RNA RNA Binding RNA Recognition Motif RNA-Binding Proteins Reporter Role Series Shapes Site Somatic Cell Structure Supporting Cell Transcript Translations cell type comparative design experimental study human disease in vivo insight mRNA Translation nervous system disorder polarized cell programs protein complex protein protein interaction recruit ribosome profiling spatiotemporal

项目摘要

SUMMARY Cellular morphology is one of the most distinctive features of somatic cells in multicellular organisms and is intimately linked with cellular function. How neurons and other polarized cells commit to their morphologies is poorly understood, but spontaneous morphogenesis of dissociated cells in culture suggest that the basic instructions for morphology are often intrinsically encoded. We previously identified a sequence-specific RNA- binding protein, Unkempt, as a factor that is essential for the establishment of the early neuronal morphology and as a protein that is capable of endowing a similar shape to cells of nonneuronal origin. Unkempt recognizes a unique binding motif predominantly within coding regions mRNAs the translation of which it suppresses. It is unclear how Unkempt regulates translation, and whether translation or another functional modality of Unkempt is critical to its induction of cell polarization. Here, we seek to solve this problem by deciphering the mechanistic basis of Unkempt-driven remodeling of cellular shape. Our preliminary studies indicate that in the broad protein-protein interaction network of Unkempt, the interaction between Unkempt’s low-complexity domain (LCD) and the CCR4-NOT complex is exquisitely required for the induction of cell morphogenesis. We propose three specific aims to investigate the molecular and cellular roles of the CCR4- NOT complex as a critical effector of Unkempt-controlled cell morphogenesis. First, we will investigate the nature of Unkempt – CCR4-NOT interactions and their impact on the fate of the targeted messages, focusing in particular on their poly(A) tail length, stability, and translation. Second, we will interrogate the recruitment and function of CCR4-NOT in Unkempt-induced cell morphogenesis. Third, we will determine the effect of post-translational modifications of Unkempt on its interactions with the CCR4-NOT complex and RNA, as well as its control of local protein translation. This study will shed light on the molecular underpinnings of the early neuronal morphogenesis and contribute to our general understanding of the cues that control cellular morphology in development and disease.

总结