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，并且作为组成型活性转录因子而不明显需要配体结合。该基因最初是通过其参与与皮肤外粘液样软骨肉瘤（EMC）相关的染色体重排而确定的，EMC是一种起源于软骨形成间充质的肿瘤。然而，实际上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，我们已经开始研究这种因子在小鼠发育过程中的时空表达，并建立小鼠中nor-1基因消融的后果。我们的初步数据表明，在胚胎中的nor-1表达与内耳形态发生和胚胎软骨形成和滑膜关节形成的关键时期密切相关。与其在发育中的内耳中的表达一致，小鼠中nor-1的消融导致异常的盘旋行为表型，这与内耳前庭器官中的原发性缺陷一致。本项目的目标是明确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。具体而言，我们将1）建立nor-1表达与前庭和耳蜗发育的分子信号之间的关系以及nor-1消融对这些通路的影响，2）通过比较nor 1 -1的表达与分化的分子标志物并分析nor 1 -1消融的表型结果，确定nor 1 -1在软骨细胞分化和滑膜关节形成和功能中的作用，以及3）确定单独的nor-1的转基因过表达是否足以改变软骨细胞分化的程序并诱导类似于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.