Molecular and Genetic Regulation of Craniofacial Development

颅面发育的分子和遗传调控

• 批准号: 7792319
• 负责人: Brian L Black
• 金额: $ 38.63万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-25 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7792319
• 关键词: Accounting; Address; Affect; Alleles; Birth; Boxing; Cell Survival; Cleft Palate; Complex; Congenital Abnormality; Defect; Development; Diagnosis; Distal; Endothelin; Endothelin Receptor; Enhancers; Environmental Risk Factor; Etiology; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Models; Genetic Transcription; Goals; Growth; Heterozygote; Homeobox; Infant; Intervention; Jaw; Live Birth; Mandible; Mesenchyme; Modeling; Molecular Genetics; Morbidity - disease rate; Mus; Mutation; Natural regeneration; Palate; Pathway interactions; Phenotype; Positioning Attribute; Prevalence; Process; Receptor Signaling; Regulation; Regulator Genes; Robin bird; Signal Pathway; Signal Transduction; Tissue Engineering; Tongue; Transcription factor genes; Transcriptional Activation; Transgenic Mice; Work; airway obstruction; base; craniofacial; dosage; feeding; in vivo; migration; mortality; mutant; novel; programs; public health relevance; repaired; response; transcription factor

DESCRIPTION (provided by applicant): Craniofacial anomalies account for nearly one-third of all birth defects and are a severe cause of morbidity and mortality in infants. In spite of their prevalence, the underlying genetic and molecular mechanisms causing most craniofacial defects remain largely unknown. The long-term goal of the proposed studies is to define the molecular and genetic pathways that control craniofacial development for the purpose of regeneration and repair, tissue engineering, and the diagnosis of and intervention into congenital craniofacial birth defects. Specifically, this application is focused on the identification of the transcriptional pathways and mechanisms involved in craniofacial development. Recent work has identified a novel genetic model for Pierre Robin Sequence (PRS) in mice. PRS occurs in about 1 in every 800 live births and is characterized by small lower jaw, improperly positioned tongue and posterior cleft of the palate, which can result in upper airway obstruction and feeding difficulties. Previously, it was thought that PRS occurred as a result of environmental factors that restrict outgrowth of the mandible, but it is now quite clear that this sequence also has an undefined genetic component(s). Mice that carry one mutant allele of Dlx5/6 locus and one mutant copy of the Mef2c allele die at birth from craniofacial defects resembling PRS. The Dlx5/6 locus encodes two Distal-less related homeobox transcription factors, while the Mef2c locus encodes a MADS box transcription factor. In addition to their genetic interaction, MEF2C and Dlx5 cooperate to induce a robust synergistic transcriptional response. The hypotheses underlying this proposal are that Dlx5/6 and MEF2C form a transcriptional complex downstream of endothelin receptor signaling, that this complex is essential for the activation of a subset of genes that are required for craniofacial development, and that mutations or aberrant expression of Dlx5/6-MEF2C target genes contributes to craniofacial anomalies such as PRS. To address these hypotheses, three specific aims are proposed. Aim 1 will define the physical and functional interaction between Dlx5 and MEF2C and how this results in transcriptional activation. The goal is to define the transcriptional mechanisms that control gene expression during craniofacial development. Aim 2 will analyze the craniofacial defects in Mef2c-Dlx5/6 double heterozygotes in detail. The goal is to identify possible cellular mechanisms underlying the mandible and palate phenotypes in double heterozygotes to understand how these processes control palate closure and jaw growth. Aim 3 will identify upstream regulators of Mef2c transcription in craniofacial mesenchyme and will determine whether Mef2c is a direct target of the endothelin signaling pathway, using a transgenic mouse approach. The goals are to place Mef2c into a transcriptional pathway and to identify the immediate transcriptional effectors of endothelin signaling in craniofacial development. PUBLIC HEALTH RELEVANCE: Craniofacial anomalies, which account for nearly one third of all birth defects and are estimated to occur in 1 every 300 live births, are a severe cause of morbidity and mortality in infants. In spite of the prevalence of craniofacial birth defects, the underlying genetic and molecular mechanisms causing these anomalies remain largely unknown. The proposed studies will contribute to the understanding of the molecular and genetic mechanisms controlling craniofacial development, which is essential for determining how to reactivate or modulate these programs for the purpose of regeneration and repair, tissue engineering, and the diagnosis of and intervention in craniofacial birth defects.

描述（由申请人提供）：颅面畸形占所有出生缺陷的近三分之一，是婴儿发病和死亡的严重原因。尽管它们很普遍，但导致大多数颅面缺陷的潜在遗传和分子机制在很大程度上仍然未知。本研究的长期目标是确定控制颅面发育的分子和遗传途径，以实现颅面再生和修复、组织工程以及先天性颅面出生缺陷的诊断和干预。具体地说，这个应用集中在识别参与颅面发育的转录途径和机制。最近的工作已经确定了一个新的遗传模型皮埃尔罗宾序列（PRS）在小鼠。每800名活产婴儿中约有1例发生PRS，其特征是下颌小、舌头位置不正确和后腭裂，可导致上呼吸道阻塞和喂养困难。以前，人们认为PRS的发生是由于环境因素限制了下颌骨的生长，但现在很清楚，这个序列也有一个未定义的遗传成分。携带一个Dlx5/6位点突变等位基因和一个Mef2c等位基因突变拷贝的小鼠在出生时死于类似PRS的颅面缺陷。Dlx5/6基因座编码两个远端无相关的同源盒转录因子，而Mef2c基因座编码一个MADS盒转录因子。除了它们的遗传相互作用外，MEF2C和Dlx5合作诱导强大的协同转录反应。基于这一假说，Dlx5/6和MEF2C在内皮素受体信号的下游形成了一个转录复合体，该复合体对于颅面发育所需的一组基因的激活是必不可少的，Dlx5/6-MEF2C靶基因的突变或异常表达有助于颅面异常，如PRS。为了解决这些假设，提出了三个具体目标。目的1将定义Dlx5和MEF2C之间的物理和功能相互作用，以及这种相互作用如何导致转录激活。目的是确定颅面发育过程中控制基因表达的转录机制。目的2将详细分析Mef2c-Dlx5/6双杂合子颅面缺陷。目的是确定双杂合子中下颌和上颚表型可能的细胞机制，以了解这些过程如何控制上颚闭合和颌骨生长。目的3将确定颅面间质中Mef2c转录的上游调控因子，并通过转基因小鼠方法确定Mef2c是否是内皮素信号通路的直接靶点。目的是将Mef2c置于转录通路中，并确定内皮素信号在颅面发育中的直接转录效应。