Control of Skeletal Growth by ATF-2

描述(由申请人提供)：控制生长板软骨细胞的进展对于正常的骨和骨髓形成是必不可少的。PTHrP受体、FGFR3受体、转化生长因子β受体II、维生素D受体和甲状腺激素受体等基因的缺失会导致小鼠生长板的紊乱和异常的软骨内成骨。人类多种遗传性和获得性骨骼疾病是由于生长板中软骨细胞增殖和成熟之间的平衡被扰乱而导致的，包括软骨发育不良、像Beckwith Wiedernann综合征这样的过度生长疾病、骨软骨瘤和其他软骨肿瘤，以及一些形式的骨关节炎。激活转录因子2(ATF-2)针对许多不同基因中的环状AMP反应元件(CRE)，导致基因转录的激活。小鼠的ATF-2基因突变导致生长板软骨细胞中没有ATF-2，软骨内骨化缺陷类似于人类软骨发育不良，这是一种由于FGFR3受体激活突变而导致的侏儒症。ATF-2基因缺陷的小鼠存活率显著降低，并表现出生长板表型，包括增殖区和肥大区的减少。该提案的总体目标是确定ATF-2在控制软骨细胞增殖和生长板进展中的作用。该提案集中在ATF-2的八个基因靶点：细胞周期蛋白D1、细胞周期蛋白A、c-Fos、c-Jun、视网膜母细胞瘤蛋白(PRB)、p107、p130和Bcl-2。除Bc l-2外，其余均直接参与细胞周期进程，因此是软骨细胞增殖的调节者。细胞凋亡发生在生长板肥大带的终末软骨细胞中，bcl2在此过程中起着调控作用。这项建议利用ATF-2缺陷小鼠的生长板进行分子分析：1)ATF-2对靶基因的直接和间接影响；2)在没有ATF-2的情况下靶基因表达减少的后果；以及3)导致正常或异常生长板软骨细胞增殖和进展的信号通路的定义。

DESCRIPTION (provided by applicant): Control of growth plate chondrocyte progression is essential for proper bone and marrow formation. Disruptions in several genes such as those for the PTHrP receptor, FGFR3 receptor, TGF beta receptor type II, vitamin D receptor, and thyroid hormone receptor result in disorganization of the growth plate and abnormal endochondral ossification in mice. Multiple human genetic and acquired skeletal disorders result from the perturbation of the balance between chondrocyte proliferation and maturation in the growth plate, including chondrodysplasias, overgrowth diseases like Beckwith Wiedernann syndrome, osteochondromas and other cartilage neoplasms, and some forms of osteoarthritis. Activating transcription factor 2 (ATF-2) targets the cyclic AMP response element (CRE) in many different genes and results in the activation of gene transcription. A mutation in the ATF-2 gene in mice results in the absence fo ATF-2 in growth plate chondrocytes and defects in endochondral ossification resembling human hypochondroplasia, a dwarfism due to activating mutations in the FGFR3 receptor. ATF-2-deficient mice have a substantially reduced survival rate, and display a growth plate phenotype that encompasses reductions in both the proliferative and hypertrophic zones. The overall goal of this proposal is to define the roles of ATF-2 in control of chondrocyte proliferation and growth plate progression. The proposal is focused on eight gene targets of ATF-2: those for cyclin D1, cyclin A, c-Fos, c-Jun, the retinoblastoma protein (pRb), p107, p130,and Bcl-2. All but Bcl-2 are directly involved in cell cycle progression, and therefore are regulators of chondrocyte proliferation. Bcl-2 plays a role in the control of apoptosis, which occurs in the terminal chondrocytes of the hypertrophic zone in the growth plate. This proposal exploits the growth plates of ATF-2-deficient mice for molecular analyses of 1) the direct and indirect effects of ATF-2 on target genes; 2) the consequences of reductions in expression of the target genes in the absence of ATF-2; and 3) the definition of signaling pathways that result in normal I or abberant growth plate chondrocyte proliferation and progression.