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Decoding neural cell fate diversity

解码神经细胞命运多样性

基本信息

批准号：
10283597
负责人：
JUDITH S EISEN
金额：
$ 40.56万
依托单位：
UNIVERSITY OF OREGON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10283597
关键词：
Address Adopted Architecture Axon Behavior Bioinformatics Brain CRISPR screen Candidate Disease Gene Cell Separation Cell Survival Cells Cessation of life Daughter Development Developmental Process Disease Elements Embryo Event Fluorescence Foundations Gene Expression Profile Gene Expression Profiling Genes Genetic In Situ Hybridization Individual Injury Ion Channel Knowledge Learning Life Modeling Molecular Motor Neurons Muscle Muscle Fibers Nervous System Physiology Nervous system structure Neurons Optics Pathway interactions Population Process Protocols documentation RNA Research Role Signal Pathway Spinal Surveys Synapses System Target Populations Techniques Testing Time Transcript Transgenic Organisms Vertebrates Zebrafish differential expression experimental study gene discovery innovation insight molecular marker nerve stem cell nerve supply neurodevelopment neuron development neuron loss single-cell RNA sequencing therapeutic target tool transcription factor

项目摘要

PROJECT SUMMARY/ABSTRACT Cell fate diversification is a critical step in producing the many neuronal subtypes required for functional circuitry in the vertebrate brain. We know a considerable amount about how neural progenitors diversify fates to form distinct daughter neurons. However, much less is known about later processes that diversity the fates of postmitotic neurons. One reason for this knowledge gap is that in most vertebrate models it is impossible to recognize and study precisely the same neurons in separate individuals, limiting predictive and statistical power. We can overcome these limitations in zebrafish by studying two adjacent, individually identifiable, spinal motoneurons. We discovered that these neurons are initially equivalent, and that interactions between them, in addition to interactions with an identified set of muscle fibers, breaks the equivalence between the two neurons and causes them to adopt distinct fates. Moreover, one of these neurons then typically dies, an important fate for sculpting brain architecture and circuitry. This is a unique situation in vertebrates, in which we can observe fate diversification as it is occurring in living embryos and predict that a neuron will die well before the process occurs, yet we still do not know the underlying molecular events. We will overcome this barrier using a variety of tools that enable us to manipulate the fates of these two neurons and single cell RNA sequencing at defined stages during the developmental process. This combination with enable us to discover genes involved in neuronal cell fate diversification as well as genes that predict neuronal cell death and survival. We plan to validate these genes using quantitative RNA in situ hybridization techniques. We will then test validated candidates using an innovative F0 CRISPR screen. Our proposed studies will reveal genes previously unknown to function during neuronal cell fate diversification, survival, and death. If successful, they will uncover genetic mechanisms of neuronal cell fate diversification with unprecedented precision, and thus will open new avenues of inquiry and deepen our understanding of neurodevelopmental mechanisms.

项目总结/文摘