Regulation of neurodevelopmental cell behaviors in Ciona

Ciona 神经发育细胞行为的调节

• 批准号: 10701717
• 负责人: Christina Donata Cota
• 金额: $ 31.36万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-12 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10701717
• 关键词: Anatomy; Anterior; Automobile Driving; Axon; Behavior; Biochemical Pathway; Biological Availability; CRISPR/Cas technology; Cell Differentiation process; Cell Lineage; Cell Polarity; Cell physiology; Cells; Central Nervous System; Chordata; Cues; Development; Disease; Distal; Dorsal; Ectoderm; Embryo; Endosomes; Ensure; Epithelium; Fluorescence Microscopy; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Genomics; Homologous Gene; Human; Human Development; Individual; Invertebrates; Knowledge; Link; Malignant Neoplasms; Maps; Membrane; Molecular; Morphogenesis; Morphology; Movement; Nervous System; Neural Crest; Neural tube; Neurites; Neuronal Differentiation; Neurons; Organism; Outcome; Paraxial Mesoderm; Pathway interactions; Peripheral; Positioning Attribute; Process; Property; Proteins; Recycling; Regulation; Reproducibility; Research; Resolution; Role; Sensory; Shapes; Side; Specific qualifier value; Spinal Ganglia; Stereotyping; Study models; Synapses; Syndrome; System; Tail; Testing; Tight Junctions; Tissues; Transcriptional Regulation; Transforming Growth Factor beta; Urochordata; Vertebrates; Work; cell behavior; cell motility; cholinergic; connectome; extracellular; genetic architecture; genome editing; in vivo; in vivo imaging; innovation; insight; knockout gene; migration; nerve stem cell; neurodevelopment; notochord; polarized cell; programs; rab GTP-Binding Proteins; receptor; response; temporal measurement; therapy development; trafficking; transcription factor; transcriptomic profiling

PROJECT SUMMARY/ABSTRACT The regulation of transient cell behaviors and regulatory “states” is indispensable for the development of multicellular organisms. Knowledge of the genetic architecture and emergent properties of these processes is also key to developing therapies for congenital diseases and neurodevelopmental syndromes based on cellular reprogramming or genome editing. The objective of this proposal is to characterize the regulation and functions of potentially important genes that control polarized neuronal migration and axon outgrowth in the Ciona larval nervous system, which shares many anatomical and molecular features with the larger systems of their close relatives the vertebrates. The central hypothesis is that these processes are controlled by precise developmental regulation of genes encoding rate-limiting components of diverse biochemical pathways, which may vary according to developmental stage and neuronal subtype. The rationale underlying the proposed research is that, by exploiting the genomic and cellular simplicity afforded by invariantly developing Ciona embryos, one can study these processes in vivo, with greater spatial and temporal resolution. With only 231 neurons and a fully mapped “connectome”, the Ciona nervous system offers a singular opportunity to understand cell behaviors and developmental trajectories in a chordate nervous system at single-cell resolution. The central hypothesis will be tested by pursuing three specific aims: 1) Testing the role of instrinsic and extrinsic TGFβ pathway components in dynamically but invariantly polarizing neuronal progenitors; 2) Investigating the causal links between regulation of effectors of receptor trafficking and precisely timed inversion of intracellular polarity and axon outgrowth orientation. 3) Investigating the role of collective epithelial sheet-like migration in precise positioning and morphogenesis of differentiated neurons, and testing the involvement of tight junction proteins in regulating this unusual mode of collective migration. These aims will be pursued using an innovative approach that combines cell lineage-specific, CRISPR/Cas9-based somatic gene knockouts and live fluorescence microscopy. The expected outcomes of the proposed work include identifying previously unrecognized functions for conserved but poorly studied genes in neurodevelopment, and understanding how precise control over neuronal subtype-specific polarized cell behaviors can be achieved through transcriptional regulation of both intrinsic and extrinsic effector genes.

项目总结/文摘