Regulation of Craniofacial Skeletal Development by Jab1

Jab1 对颅面骨骼发育的调节

• 批准号: 7797581
• 负责人: Guang Zhou
• 金额: $ 11.66万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7797581
• 关键词: Address; Affect; Animals; Apoptosis; Birth; Breeding; COPS5 gene; Cartilage; Cell Cycle Regulation; Cell Differentiation process; Cell Proliferation; Cells; Chondrocytes; Cleidocranial Dysplasia; Complex; Congenital Abnormality; Craniofacial Abnormalities; Defect; Development; Developmental Process; Diagnosis; Embryo; Embryonic Development; Epiphysial cartilage; Etiology; Gene Expression; Genetic; In Situ; Inherited; Integrins; Light; Limb structure; Molecular; Molecular Genetics; Morphogenesis; Mus; Mutant Strains Mice; Mutation; Neural Crest Cell; Osteoblasts; Osteogenesis; Pathogenesis; Perinatal; Phenotype; Plants; Play; Proteins; Regulation; Research; Role; Runx2 protein; Screening procedure; Series; Signal Transduction; Skeletal Development; System; Tooth structure; Transgenic Mice; Transgenic Organisms; Yeasts; base; bone; chondrodysplasia; cofactor; craniofacial; in vivo; insight; mouse model; mutant mouse model; novel; postnatal; public health relevance; research study; skeletal; skeletal disorder; skeletal dysplasia; skeletogenesis; tool; transcription factor; tumorigenesis; yeast two hybrid system

DESCRIPTION (provided by applicant): Craniofacial abnormalities represent a broad and complex class of birth defects and understanding their genetic basis is essential for their diagnosis and treatment. Despite much recent progress in understanding their etiology, many facets of their pathogenesis, which often involves a combination of environmental and genetic factors, remain poorly understood. We have recently identified transcriptional cofactor Jab1 as a novel interacting protein for Runx2, a mater regulator for skeletogenesis. Jab1 is highly conserved with over 60% identity between animal and plant counterparts. It plays essential roles during various developmental processes by modulating other transcription factors function. Jab1 is broadly expressed during embryogenesis including in the chondrocytes and osteoblasts. However, its role in cartilage and bone formation remains mostly unknown. Interestingly, in our preliminary study, loss of Jab1 specifically in chondorcytes with loxP/Cre system led to lethal chondrodysplasia at birth in mice, demonstrating that Jab1 is essential for proper cartilage formation in vivo. Furthermore, deletion of Jab1 specifically in osteo-chondroprogenitor cells results in extremely shortened limbs postnatally. Thus, we hypothesize that Jab1 plays important roles in both embryonic and postnatal skeletogenesis, including craniofacial skeletal development, by modulating the expression of genes involved in cell differentiation, cell proliferation, and apoptosis. Each of our Specific Aims will address specifically the role of Jab1 in craniofacial skeletal development with various mouse genetic and histological tools. Specific Aim 1 will determine the effect of loss of Jab1 specifically in chondrocytes with histological and in situ analysis in Jab1flox/flox; Col2a1-Cre mice. Specific Aim 2 will determine the role of endogenous Jab1 in craniofacial development by deleting Jab1 specifically in neural crest cells with Wnt1-Cre transgenic mice. Specific Aim 3 will determine the function of Jab1 in postnatal endochondral ossification with Col2a1-Cre-ER transgenic lines to induce the Jab1 deletion postnatally in a temporally controlled manner and study its effect on craniofacial morphogenesis and growth plate formation. Overall, this study will further our understanding of the genetic factors affecting craniofacial development and also generate useful mutant mouse models for craniofacial defect and chondrodysplasia research. PUBLIC HEALTH RELEVANCE: Transcriptional co-factor Jab1 plays essential roles during normal development and tumorigenesis by modulating the functions of other transcription factors. Therefore, a better understanding of the role of Jab1 in skeletogenesis, especially craniofacial development, will provide us an important insight into the molecular and genetic basis of craniofacial abnormalities and chondrodysplasia.

描述（由申请人提供）：颅面异常代表着广泛而复杂的先天缺陷类别，了解其遗传基础对于他们的诊断和治疗至关重要。尽管在理解其病因方面取得了很多进展，但其发病机理的许多方面通常涉及环境和遗传因素的结合，但人们的理解仍然很少。我们最近将转录辅因子jab1识别为一种新型的相互作用蛋白，用于Runx2，runx2是用于骨骼生成的MATER调节剂。 JAB1高度保守，动物和植物对应物之间的身份超过60％。通过调节其他转录因子功能，它在各种发育过程中起着重要作用。 JAB1在胚胎发生过程中广泛表达，包括在软骨细胞和成骨细胞中。然而，它在软骨和骨形成中的作用仍然是未知的。有趣的是，在我们的初步研究中，小鼠出生时出生时具有LOXP/CRE系统的软骨中的JAB1损失导致致命的软骨发育不良，这表明JAB1对于体内适当的软骨形成至关重要。此外，在骨 - 核元基因细胞中特别删除JAB1，导致肢体产后极度缩短。因此，我们假设JAB1通过调节与细胞分化，细胞增殖和凋亡有关的基因的表达来调节基因的表达，在包括颅面骨骼发育在内的胚胎和产后骨骼生成中都起着重要作用。我们的每个特定目标都将特别介绍JAB1在颅面骨骼发育中的作用，并使用各种小鼠遗传学和组织学工具。具体目标1将确定JAB1在软骨细胞中的损失的影响，并在Jab1flox/Flox中进行组织学和原位分析； COL2A1-CRE小鼠。特定的目标2将通过删除具有Wnt1-Cre转基因小鼠的神经rest细胞中的JAB1来确定内源性JAB1在颅面发育中的作用。具体的目标3将用COL2A1-CRE-CRE-CRE-CRE-CRE-CRE-CRE-ERS基因线在产后内软骨后骨化中的功能，以时间控制的方式诱导JAB1缺失，并研究其对颅骨形态发生和生长板形成的影响。总体而言，这项研究将进一步了解影响颅面发育的遗传因素，并为颅面缺陷和软骨发育不全研究产生有用的突变小鼠模型。 公共卫生相关性：转录共同因素JAB1通过调节其他转录因子的功能，在正常发育和肿瘤发生过程中起着重要作用。因此，更好地了解JAB1在骨骼生成中的作用，尤其是颅面发育，将为我们提供对颅面异常和软骨增生的分子和遗传基础的重要见解。