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Regulation of Cranial Mesenchyme Expansion Driving Neural Fold Elevation

颅间充质扩张驱动神经褶皱抬高的调节

基本信息

批准号：
9893986
负责人：
Irene E Zohn
金额：
$ 38.38万
依托单位：
CHILDREN'S RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9893986
关键词：
Address Alleles Anencephaly Automobile Driving Biochemical Biological Assay Candidate Disease Gene Cell Lineage Cell division Cells Cephalic Cessation of life Congenital Abnormality DNA Sequence Alteration Data Development Disease Embryo Failure Genes Genetic Genetic Counseling Heat-Shock Proteins 90 Histologic Human Image Knowledge Label Laboratories Light Link Mediating Mesenchyme Microscopy Molecular Morphogenesis Movement Mus Mutant Strains Mice Mutation Neural Crest Neural Fold Neural Tube Closure Neural Tube Defects Paraxial Mesoderm Pathogenicity Pathway interactions Patients Pattern Pharmacology Population Process Production Regulation Resolution SOX1 gene Series Signal Transduction Structural Congenital Anomalies Study models Testing Time Tissue Recombination Tissues Tretinoin Ursidae Family Variant Work base cell motility cell type defined contribution disability embryo cell experimental study extracellular gain of function imaging approach inhibitor/antagonist innovation insight loss of function mutation migration mouse model mutant mutant mouse model neural plate novel relating to nervous system tool

项目摘要

Project Summary/Abstract Neural tube defects (NTDs) are among the most common structural birth defects in humans and result in long- term disability or even death; yet, the underlying genetic causes remain largely unknown. Addressing this gap in knowledge is best achieved in the context of understanding the mechanisms mediating both normal and abnormal development. Experiments conducted nearly 40 years ago indicate that expansion of the cranial mesenchyme, a cell population that resides beneath the neural plate, is required for elevation of the cranial neural folds and neural tube closure. Yet, little is known regarding how expansion of the cranial mesenchyme drives neural fold elevation and how this process can be disrupted to cause NTDs. Moreover, few genes have been implicated in this process. In this proposal we present a novel mouse model of NTDs with a mutation in the Hectd1 gene and describe approaches that will significantly advance our understanding of how cranial mesenchyme expansion can be disrupted contributing to NTDs. Based on our previous and preliminary data we hypothesize that eHSP90 secreted from Hectd1 mutant NC-CM stimulates increase movement of the CM interfering with expansion of the PM-CM and disrupting neural fold elevation (Specific Aims 1 & 2). We further hypothesize that HECTD1 sequence variants associated with human NTDs employ the same pathogenic mechanism (Specific Aim 3). We will test these hypotheses using a combination of innovative tools including: (1) advanced imaging approaches to visualize, at unprecedented resolution expansion of the cranial mesenchyme in real time during neural fold elevation, (2) fluorescently labeled eHSP90 probes to elucidate spatial and temporal patterns of pathogenic eHSP90 production, (3) an ex vivo cranial mesenchyme explant assay amenable to experimental manipulation, (4) a novel allelic series of mouse lines and (5) pharmacological inhibitors to test whether eHSP90 mediates failure of cranial mesenchyme expansion and neural fold elevation in Hectd1 mutant embryos. These innovative tools will be combined with well-established conditional genetic, histological and embryological approaches to delineate, in unprecedented detail, expansion of cranial mesenchyme in normal neural fold elevation and how this process goes awry during failed cranial mesenchyme expansion responsible for NTDs in the Hectd1 mutant embryo. This information will be used to determine the impact of predicted pathogenic sequence variants of HECTD1 identified in human NTD cases and ascertain if variants disrupt HECTD1 function and contribute to NTDs in human patients.

项目总结/文摘