Regulation of Craniofacial Skeletal Development by Jab1

描述（由申请人提供）：颅面畸形代表了广泛而复杂的出生缺陷类别，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（通常涉及环境和遗传因素的结合）仍然知之甚少。我们最近发现转录辅助因子Jab1是Runx2的一种新的相互作用蛋白，Runx2是骨骼形成的物质调节因子。Jab1具有高度保守性，在动物和植物间同源性超过60%。它通过调节其他转录因子的功能，在各种发育过程中发挥重要作用。Jab1在胚胎发生过程中广泛表达，包括软骨细胞和成骨细胞。然而，它在软骨和骨形成中的作用仍然未知。有趣的是，在我们的初步研究中，Jab1在具有loxP/Cre系统的软骨细胞中的特异性缺失导致小鼠出生时致命的软骨发育不良，这表明Jab1对体内正常软骨形成至关重要。此外，在骨-软骨祖细胞中特异性地缺失Jab1会导致出生后肢体极度缩短。因此，我们假设Jab1通过调节参与细胞分化、细胞增殖和凋亡的基因的表达，在胚胎和出生后的骨骼发生，包括颅面骨骼发育中发挥重要作用。我们的每个特定目标都将通过各种小鼠遗传和组织学工具具体解决Jab1在颅面骨骼发育中的作用。特异性Aim 1将通过组织和原位分析确定Jab1在软骨细胞中特异性缺失的影响；Col2a1-Cre老鼠。特异性Aim 2将通过在Wnt1-Cre转基因小鼠中特异性删除神经嵴细胞中的Jab1来确定内源性Jab1在颅面发育中的作用。特异性Aim 3将利用Col2a1-Cre-ER转基因系确定Jab1在出生后软骨内成骨中的功能，以一种时间可控的方式诱导出生后Jab1缺失，并研究其对颅面形态发生和生长板形成的影响。总的来说，本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。

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.