Regulation of Craniofacial Skeletal Development by Jab1

Jab1 对颅面骨骼发育的调节

• 批准号: 7660695
• 负责人: Guang Zhou
• 金额: $ 11.78万
• 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/7660695
• 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)：颅面畸形是一类广泛而复杂的出生缺陷，了解其遗传基础对其诊断和治疗至关重要。尽管最近在了解其病因方面取得了很大进展，但其发病机制的许多方面仍然知之甚少，这些方面往往涉及环境和遗传因素的组合。我们最近发现转录辅因子Jab1是一种新的与Runx2相互作用的蛋白，Runx2是一种骨骼形成的物质调节因子。Jab1基因高度保守，与动物和植物的同源性超过60%。它通过调节其他转录因子的功能，在不同的发育过程中发挥重要作用。Jab1在胚胎发育过程中广泛表达，包括在软骨细胞和成骨细胞中表达。然而，它在软骨和骨形成中的作用大多还不清楚。有趣的是，在我们的初步研究中，通过loxP/Cre系统特异性地在软骨细胞中缺失Jab1导致小鼠出生时致死性软骨发育不良，表明Jab1对于体内正常的软骨形成是必不可少的。此外，特定于骨软骨前体细胞的Jab1基因缺失会导致出生后肢体极短。因此，我们推测Jab1通过调节细胞分化、细胞增殖和细胞凋亡相关基因的表达，在胚胎和出生后的骨骼发生中发挥重要作用，包括头面部骨骼发育。我们的每个具体目标都将通过各种小鼠遗传和组织学工具具体说明Jab1在头面部骨骼发育中的作用。特定目的1将通过组织学和原位分析来确定Jab1在软骨细胞中特异性丢失的影响；特定目的2将通过在WNT1-Cre转基因小鼠的神经脊细胞中特异性地删除Jab1来确定内源性Jab1在颅面发育中的作用。本研究的目的3是利用转COL2a1-CRE-ER基因的转基因细胞，时间可控地诱导Jab1基因在生后软骨内成骨中的作用，并研究其对颅面形态发生和生长板形成的影响。总体而言，这项研究将进一步加深我们对影响颅面发育的遗传因素的理解，并为颅面缺陷和软骨发育不良的研究提供有用的突变小鼠模型。 与公共健康相关：转录辅助因子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发挥重要作用。因此，深入了解Jab1在骨骼发育，尤其是颅面发育中的作用，将为我们深入了解颅面畸形和软骨发育不良的分子和遗传学基础提供重要的信息。