Developmental role of the nuclear receptor Nor-1

点击翻译按钮获取中文摘要

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.