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The Role of SPECC1L cytoskeletal protein in craniofacial development and malformation

SPECC1L细胞骨架蛋白在颅面发育和畸形中的作用

基本信息

批准号：
9158833
负责人：
Irfan Saadi
金额：
$ 32.51万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9158833
关键词：
Adherens Junction Adhesions Affect Alleles Attenuated Bilateral Biological Assay Branchial arch structure Cell Adhesion Cell Communication Cell Polarity Cell membrane Cell physiology Cell-Cell Adhesion Cells Cephalic Chemicals Cleaved cell Collaborations Complex Congenital Abnormality Craniofacial Abnormalities Cultured Cells Cytoskeletal Proteins Data Defect Destinations Disease Embryo Embryonic Development Epithelial Exencephalies Exhibits Eye Face Family Future Genes Genetic Goals Human Image In Vitro Intercellular Junctions Japan Knowledge Life Link Live Birth Measures Mediating Mediation Medical Membrane Mesenchymal Modeling Molecular Morphogenesis Movement Mus Mutate Mutation Neural Crest Neural Crest Cell Neural Fold Neural Tube Closure Neural tube Neuroectoderm Neuroepithelial Neuroepithelial Cells Operative Surgical Procedures Opitz syndrome Oral Oral cavity Orbital separation excessive Outcome Palate Pathogenesis Pathway interactions Patients Perinatal Persons Phenotype Play Prevention strategy Productivity Proteins Proto-Oncogene Proteins c-akt Role Sampling Services Severities Signal Transduction Staging Stream Teebi syndrome Testing Therapeutic Tissues Transmission Electron Microscopy Ubiquitination base cell behavior cell motility cleft lip and palate craniofacial craniofacial development density dosage improved in vivo inhibitor/antagonist insight life time cost malformation migration mouse model mutant neural plate new therapeutic target novel orofacial cleft palatal shelves palatogenesis postnatal small molecule

项目摘要

PROJECT SUMMARY Orofacial clefts are among the most common birth defects in the U.S., occurring in 1/800 live-births. The lifetime cost for medical treatment, educational services and lost productivity averages more than $100,000 per affected person. While a number of contributory genes have been identified, there is a continued need to understand the underlying pathogenetic mechanisms. We identified the first de novo mutations in a novel cytoskeletal SPECC1L gene in patients with oblique facial clefts. Recent identification of SPECC1L mutations in patients with syndromic and nonsyndromic cleft lip and palate suggests that insights into the cellular and molecular mechanism of SPECC1L function will be directly relevant to both severe and common facial malformations. Our data show that Specc1l is expressed in the neural folds at E8.5, including in pre-migratory cranial neural crest cells (CNCCs). Later at E9.5, it is expressed in post-migratory CNCCs, and in the branchial arches at E10.5. To study SPECC1L function, we have generated severe, hypomorphic and conditional mouse alleles of Specc1l deficiency. The severe mouse allele is embryonic lethal at E9.5 with defective neural tube (NT) closure and incomplete delamination of post-migratory CNCCs. The hypomorphic allele shows incompletely penetrant perinatal exencephaly phenotype. Moderate mutants with one hypomorphic and one severe allele show highly penetrant palate closure delay. In addition, SPECC1L-deficient cells show altered adherens junctions (AJs) and reduced PI3K-AKT signaling, both in vitro in cultured cells and in vivo in Specc1l mutant tissue. Modulation of cell-cell contacts is important not only for CNCC delamination from the neuroectoderm, but also for “collective” migration of CNCCs to their defined destinations. The central hypothesis of this project is that SPECC1L modulates cell adhesion and collective migration by regulating the density of epithelial and mesenchymal cell-cell contacts through PI3K-AKT signaling. In Aim 1, we propose to investigate the effect of Specc1l dosage on craniofacial development using our hypomorphic, severe, and conditional mouse alleles. In Aim 2, we will investigate SPECC1L mediation of AJ stability and PI3K-AKT signaling using small molecule modulators of PI3K-AKT pathway. We will also explore the mechanism underlying SPECC1L mediation of AKT stability. In Aim 3, we will use live-imaging to quantitatively assess changes in collective cell behavior. Analyses will be conducted in ex vivo cultured E8.5 neural plate explants, with CNCCs marked with Wnt1-Cre or Sox10-Cre. Successful completion of these studies will establish novel SPECC1L-based links between AJs, cell polarity and PI3K-AKT signaling during facial morphogenesis and palate closure. Understanding the correlation between SPECC1L dosage or functional deficiency and collective cell migration will provide targets for future therapeutic or preventative strategies against orofacial clefting.

项目总结