Developmental role of the nuclear receptor Nor-1

我们研究的总体目标是建立孤儿核受体NOR-1的发育和生理功能。NOR-1是核受体超家族的成员之一，是一种结构性的活性转录因子，不需要明显的配体结合。该基因最初是通过参与与骨骼外粘液样软骨肉瘤(EMC)相关的染色体重排而被发现的，EMC是一种起源于软骨形成间充质的肿瘤。然而，几乎没有关于这种核受体在体内的功能的信息。为了深入了解NOR-1的发育和生理作用，我们已经开始研究NOR-1的这种发育和生理作用的时空表达，我们已经开始检测这一因子在小鼠发育过程中的时空表达，并建立NOR-1在小鼠中的遗传消融的后果。我们的初步数据表明，NOR-1在胚胎中的表达与内耳形态发生、胚胎软骨发生和附件骨中滑膜关节形成的关键期密切相关。与其在发育中的内耳中的表达一致，消融NOR-1在小鼠体内会导致异常的旋转行为表型，这与内耳前庭器官的原发缺陷一致。该项目的目标是确定NOR-1在内耳和骨骼发育中的具体作用，并确定NOR-1所在的分子发育信号通路。具体地说，我们将1)建立NOR-1的表达与前庭和耳蜗区发育的分子信号之间的关系以及NOR-1消融在这些途径上的后果；2)通过比较Nor1-1的表达与分化的分子标记以及分析NOR-1消融的表型后果，确定NOR-1在软骨细胞分化和滑膜关节形成和功能中的作用；3)确定NOR-1的转基因过表达是否足以改变软骨细胞的分化程序，诱导类似EMC的表型。

The overall objective of our research is to establish the developmental and physiological functions of the orphan nuclear receptor, nor-1. Nor-1 is a member of the nuclear receptor superfamily and acts as a constitutively active transcription factor without an apparent requirement for ligand binding. The gene was originally identified through its involvement in a chromosomal rearrangement associated with extraskeletal myxoid chondrosarcoma (EMC), a tumor that originates in cartilage forming mesenchyme. However, virtually no information is available on the functions of this nuclear receptor in vivo. In order to gain insights into the developmental and physiological role of nor-1, we have begun to examine the spatiotemporal expression of this developmental and physiological role of nor-1, we have begun to examine the spatiotemporal expression of this factor during murine development and to establish the consequences of genetic ablation of nor-1 in mice. Our preliminary data indicates that nor-1 expression in the embryo is closely associated with the critical periods of inner ear morphogenesis and embryonic chondrogenesis and synovial joint formation in the appendicular skeleton. Consistent with its expression in the developing inner ear, ablation of nor-1 in mice results in an abnormal circling behavior phenotype that is consistent with a primary defect in the vestibular apparatus of the inner ear. The goal of this project is to define the specific role of nor-1 in inner ear and bone development and it identify the molecular development signaling pathways in which nor-1 resides. Specifically, we will 1) establish the relationship between nor-1 expression and molecular signals of vestibular and cochlear development and the consequences of nor-1 ablation on these pathways, 2) establish the role of nor1-1 in chondrocyte differentiation and synovial joint formation and function by comparison of its expression with molecular markers of differentiation and analysis of the phenotypic consequences of nor-1 ablation and 3) determine whether transgenic over- expression of nor-1 alone is sufficient to alter the program of chondrocyte differentiation and induce a phenotype similar to EMC.