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The role of the Foxi3 transcription factor in craniofacial microsomia

Foxi3转录因子在颅面微小症中的作用

基本信息

批准号：
10666893
负责人：
Andrew K Groves
金额：
$ 59.14万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-15 至 2028-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10666893
关键词：
Address Affect Alleles Animal Model Binding Bioinformatics Biological Assay Branchial arch structure Cells Cephalic Chromatin Cleft lip with or without cleft palate Complex Congenital Abnormality Craniofacial Abnormalities Craniosynostosis Data Defect Dermoid Cyst Development Disease Disease model Ear ossicles Ectoderm Embryo Endoderm Exhibits External Ear Face Facial asymmetry Family Fetal Development First Pharyngeal Arch GATA3 gene Gene Expression Gene Expression Profiling Genes Genetic Genetic Transcription Goldenhar Syndrome Health Heterogeneity Heterozygote Human Individual Individuation Inherited Jaw Knockout Mice Live Birth Mandible Modeling Molecular Morphology Mus Mutant Strains Mice Mutate Mutation Neural Crest Neural Crest Cell Pathogenicity Patients Pattern Pharyngeal pouch Pharyngeal structure Phenotype Role Second branchial arch structure Series Severities Side Signal Transduction Symptoms Testing Time Tissues Toxic Environmental Substances Variant Wild Type Mouse cleft lip and palate conditional mutant craniofacial craniofacial development craniofacial microsomia gene interaction gene regulatory network genetic disorder diagnosis genetic variant genome wide association study human model insight member microtia middle ear migration mouse genetics mouse model mutant single-cell RNA sequencing spine bone structure transcription factor virulence gene

项目摘要

PROJECT SUMMARY Craniofacial abnormalities are some of the most common birth defects. Although cleft lip and/or palate and craniosynostosis are the most common craniofacial defects, craniofacial microsomia (CFM) is estimated to be the third most prevalent cranial anomaly, occurring at between 1 in 3000 – 1 in 6000 live births. Although the symptoms of CFM can vary widely in severity, they share a variety of features consistent with abnormal development of first and second pharyngeal arches, including a shortening of the mandible, microtia, preauricular tags and epibulbar dermoids. These defects are typically, but not exclusively unilateral, and although some families presenting with CFM have been identified, most are considered sporadic and have no genetic diagnosis. Difficulties in understanding the origins of CFM include its heterogeneity, the lack of clear underlying molecular mechanisms and the paucity of good animal models for these disorders. We have identified a transcription factor, Foxi3, that is expressed early and broadly in pharyngeal ectoderm and endoderm, and is later restricted to the pharyngeal pouches and clefts. Foxi3 mutant mice show severe defects in most pharyngeal arch derivatives – for example, the mutants lack much of the lower jaw, and have a complete loss of the middle ear ossicles and the external ear. Recently, our colleagues found over 20 human variants in Foxi3 associated with craniofacial defects including CFM and microtia, and our preliminary data suggests these defects can be modeled in mice carrying some of these variants. Moreover, the Gata3 transcription factor, which has been associated with CFM in genome-wide association studies, is co-expressed with Foxi3 in several developing cranial tissues and has also recently been shown to cause CFM phenotypes when mutated in mice. This raises the possibility that Foxi3 and Gata3 interact genetically during craniofacial development. In this proposal, we will first attempt to create a mouse model of CFM using Foxi3 mutant alleles created in our lab and Gata3 mutant alleles characterized by our collaborators. Second, we will perform a bioinformatic analysis of the gene regulatory networks controlled by Foxi3 and Gata3, by analyzing gene expression in pharyngeal tissue from Foxi3 homozygous mutants, heterozygous mutant and wild type mice, and by performing CUT&RUN on pharyngeal tissue to identify direct targets of Foxi3 and Gata3. Finally, we will address the role of Foxi3 during early craniofacial development by performing conditional deletions of Foxi3 in pharyngeal ectoderm and endoderm and determining its contribution to normal craniofacial development in each tissue.

项目总结