Transcriptional control of epithelial behaviors that drive mammalian neural tube closure

驱动哺乳动物神经管闭合的上皮行为的转录控制

• 批准号: 9041647
• 负责人: Lee A. Niswander
• 金额: $ 31.44万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9041647
• 关键词: Abbreviations; Actins; Address; Affect; Alleles; Animal Model; Attention; Binding; Binding Sites; Biology; Brain; CDH1 gene; CRISPR/Cas technology; Cell Adhesion; Cell Shape; Cell model; Cells; Cephalic; Characteristics; Child; Child Mortality; Clinical; Collaborations; Complex; Computer Simulation; Congenital Abnormality; Consensus; Coupling; DNA Binding; Defect; Distal; Dorsal; Drosophila genus; E-Cadherin; Ectoderm; Ectoderm Cell; Embryo; Embryonic Development; Emotional; Epithelial; Equilibrium; Ethylnitrosourea; Evaluation; Event; Exencephalies; Face; Failure; Family; Family member; Filopodia; Foundations; Gene Activation; Gene Expression Regulation; Gene Targeting; Genes; Genetic; Genetic Screening; Genetic Transcription; Genetic study; Goals; Health; Homologous Gene; Human; Human Genetics; Image; Knowledge; Lead; Life; MAPK8 gene; Malignant Neoplasms; Mediating; Membrane; Mesenchymal; Methods; Molecular; Morphogenesis; Mus; Mutation; Neural Crest; Neural Crest Cell; Neural Fold; Neural Tube Closure; Neural Tube Defects; Neural Tube Development; Neural tube; Neuraxis; Nucleotides; Pathway interactions; Pattern; Phenotype; Process; Public Health; Recycling; Reporter; Research; Role; Sampling; Signal Pathway; Signal Transduction; Site; Somatotropin-Releasing Hormone; Specificity; Spinal; Spinal Cord; Spinal Dysraphism; Surface Ectoderm; Testing; Time; Tissues; Tomatoes; Transcription Factor AP-1; Transcriptional Regulation; Translating; Tube; Variant; cancer therapy; cell behavior; cell growth regulation; critical developmental period; driving behavior; embryo tissue; epithelial to mesenchymal transition; fly; gene function; gene repression; insight; knock-down; meetings; mortality; mouse model; mutant; neural plate; new technology; novel; preference; prevent; programs; regional difference; relating to nervous system; repaired; research study; seal; transcription factor; transcriptome

 DESCRIPTION (provided by applicant): Failure of neural tube closure is a devastating birth defect. Research in the Niswander lab has provided significant insights into the molecular and cellular regulation of NT closure. We have created and studied mouse models with neural tube defects (NTDs) to elucidate the molecular foundations of NT closure. Moreover, we have created robust and novel technology to visualize NT closure in a living mammalian embryo. Our dynamic imaging and key genetic mutants have focused attention on the little studied but critical role for the non-neural ectoderm (NNE) in NT closure. In addition we developed methods to specifically isolate NNE cells to provide a refined and robust platform to study the biology of the NNE. Here we will build upon our unique perspective and turn our attention to spinal NTDs, to provide insight into the most common type of NTD in humans, and to two genetic pathways that are associated with spina bifida in mice and humans. Aim 1 will test the hypothesis that the two closely related Grainyhead-like (GRHL) transcription factors, GRHL2 and GRHL3, differentially control cranial and spinal NT closure through unique and differential activation of target genes, in part mediated by interaction with the JNK signaling pathway that activates the AP1 (cJUN/cFOS) transcription factor. Aim 2 will extend our live platform to test the hypothesis that GRHL-regulated NNE transcriptional programs drive NT closure by controlling cell adhesion, recycling of membrane components, cell shape changes, and/or actin dynamics. Aim 3 will combine our comprehensive molecular and cellular insights with novel unpublished analyses of hundreds of NTD samples to test the hypothesis that mutations identified in GRHL3 and the JNK pathway are causative for spinal NTDs in humans. Relevance of research to public health: The proposed experiments will lead to new cellular and molecular insights into the causes of caudal NTDs, the most common type of NTD and which leads to a profoundly important and frequently disrupted aspect of mammalian embryogenesis. Moreover, our studies will impart novel insights into the general mechanisms of embryonic tissue fusion including the face and body wall. The insights gained here may lead to therapies of general application for treatment of embryonic tissue closure defects that together represent a significant percentage of human birth defects. Abbreviations used in proposal: CDH1 Cadherin1 or E-cadherin EMT Epithelial-to-mesenchymal transition GRHL Grainyhead-like (GRH is the fly homolog) KD Knock-down mT/mG Membrane tomato/membrane GFP fluorescent reporter, GFP expression is activated by Cre NNE Non-neural or surface ectoderm NT Neural tube NTD Neural tube defect Grhl2-null: We will use Grhl21Nisw allele that we isolated in our ENU-screen and which has the same phenotype as other Grhl2 null alleles. Grhl3-Cre: We will use Grhl3-Cre which generates a null allele (obtained from S. Coughlin; Grhl3tm1(cre)Cgh).