Progenitor Regulation Underlying Cortical Interneuron Specification

皮质中间神经元规范的祖细胞调节

• 批准号: 10377391
• 负责人: MARGARET ELIZABETH ROSS
• 金额: $ 56.3万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10377391
• 关键词: Address; Adopted; Affect; Behavior; Biochemical Genetics; Brain; CCND1 gene; CCND2 gene; CRISPR/Cas technology; Cell Cycle; Cell Cycle Progression; Cell Cycle Proteins; Cell Polarity; Cell division; Cells; Chromosome Mapping; Complex; Computer Models; Coupling; Cyclin D1; Data; Development; Dorsal; Embryo; Embryonic Development; Epilepsy; Excision; Exhibits; Functional disorder; G1 Phase; Ganglia; Gene Expression; Generations; Genomics; Goals; Histologic; Human; Interneurons; Knowledge; Label; Laboratories; Link; Medial; Modeling; Molecular; Mosaicism; Mutation; Nature; Neurons; Outcome; Output; Parvalbumins; Pattern; Production; Property; Prosencephalon; Proteins; Radial; Regulation; Rodent Model; Schizophrenia; Somatostatin; Surface; Technology; Testing; Time; Trees; Ventricular; autism spectrum disorder; base; brain malformation; differential expression; excitatory neuron; genetic approach; genome editing; insight; mouse genetics; mutant; nerve stem cell; neuropsychiatric disorder; operation; progenitor; programs; self-renewal; single-cell RNA sequencing; stem; stem cells; subventricular zone; transcription factor; transcriptome sequencing; virtual

PROGENITOR REGULATION UNDERLYING CORTICAL INTERNEURON SPECIFICATION Inhibitory GABAergic interneurons modulate complex cortical circuit operation. Most cortical interneurons originate from medial ganglionic eminence (MGE) progenitors that express the transcription factors, NKX2.1 in the ventral MGE and NKX6.2 in the dorsal MGE. While excitatory principal neuron production has been extensively studied, understanding of interneuron genesis, particularly the behavior and regulation of MGE progenitors, remains very limited. The proposed project addresses this outstanding knowledge gap. Although mature cortical interneurons are highly diverse, primary decisions to adopt a glial or somatostatin (SOM+) or parvalbumin (PV+) expressing neuronal fate are made as progenitors in the MGE. Based on strong preliminary data from the Shi and Ross laboratories, we hypothesize that a tight spatial and temporal regulation of the behavior and gene expression properties of MGE progenitors is essential for proper production of interneurons destined for the cortex. The project encompasses two major goals: Aim 1 probes the functional interactions between progenitor cell polarity determinant, partition defective 3 (PARD3), and G1-phase active cell cycle proteins, cyclins D1 (cD1) vs. D2 (cD2), in regulating MGE cell division, testing 2 hypotheses: 1a. MGE progenitor division modes and dynamics are spatially and temporally regulated to generate proper PV+ and SOM+ interneuron numbers. Retroviral and MADM technologies with computational modeling will be used to determine spatial (dorsal vs. ventral) and temporal dynamics of MGE radial glial progenitor (RGP) and intermediate progenitor cell (IPC) division modes and interneuron output. 1b. Differential interactions between PARD3 and cD1 vs. cD2 coordinate MGE progenitor division mode and dynamics to regulate proper PV+ vs. SOM+ fates. Studies pursue differential interactions between PARD3 and cD2 vs. cD1 in governing division mode, dynamics, and cortical interneuron output of MGE RGPs and IPCs. Aim 2 explores the core molecular program regulating the spatial and temporal behavior of MGE RGPs and IPCs using 10X Genomics-based single cell RNA sequencing of wildtype, cD2–/–, cD1–/–, Pard3 cKO and Pard3cKO;cD2–/– double mutants. Hypothesis: MGE output depends on gene expression defining cD1 and cD2 dependent progenitor pools, their division mode and dynamics. Expression networks will be validated by histological and molecular manipulation, including CRISPR/Cas9 genome editing of candidates for key drivers of MGE progenitor specification and whose expression is altered in cD1 or cD2 and Pard3 mutant MGE. The project will address a substantial knowledge gap regarding cortical interneuron genesis and provides a fundamental framework for the spatial and temporal regulation of MGE progenitors, elucidating their division mode and dynamics, their interneuron output, and the underlying core program coordinating MGE progenitor division regulation and interneuron specification.

皮层中间神经元规范下的祖细胞调控