Elucidation of the role of Creb5 in promoting the formation and patterning of the intervertebral disc

点击翻译按钮获取中文摘要

Project Summary/Abstract. Spine diseases, including intervertebral disc degeneration, facet joint syndrome, and scoliosis, are common diseases. Both intervertebral disc degeneration and facet joint syndrome, as well as scoliosis, are frequently associated with/or may lead to chronic low back pain, which is very common, causing more global disability than any other condition. The broad, long-term goal of this project is to develop a comprehensive understanding of both the specification of the cell identity and the regulatory network that regulates the formation and patterning of the intervertebral disc, which plays a pivotal role in spinal function and is subject to developmental disease, degenerative disease, and injury. However, like articular cartilage after damage, intervertebral disc cells do not repair/regenerate well. Thus, it’s critical to identify both the transcription factors and/or the signaling molecules that determine different cell types (including stem/progenitors) in the intervertebral disc to develop different strategies to treat spine disease. My recent findings have indicated that the transcription factor Creb5 is specifically expressed in intervertebral mesenchymal cells before IVD formation; is subsequently expressed in all the cells in the annulus fibrosus, including both the inner annulus fibrosus (IAF) and the outer annulus fibrosus (OAF) after IVD formation; and is also expressed in facet joints. Most significantly, I have found that the morphology of the annulus fibrosus cells is significantly altered in mice engineered to lack Creb5 function; and that expression of both Prg4/lubricin and the WNT antagonist Wif1 (Wnt inhibitor factor 1) are dramatically decreased in the intervertebral discs of these mice. Thus, my findings indicate that Creb5 is necessary to maintain the proper morphology of the intervertebral disc, and is critical to drive expression of both Prg4/lubricin and Wif1 in the intervertebral disc. Consistent with the importance of Creb5 in the IVD, a genome-wide association study identified Creb5 as a susceptibility locus for adolescent idiopathic scoliosis in Japan. A more recent genome-wide association study identified Creb5 as a susceptibility locus associated with surgery for degenerative rotator cuff disease, which is most often caused by progressive wear and tear of another fibrous connective tissue (tendon). As Creb5 is specifically expressed in the intervertebral mesenchymal (IM) that gives rise to the intervertebral disc, in facet joints, and in all the cells of annulus fibrosus, I hypothesize that Creb5 plays a critical role in the spine and propose to further investigate the role of Creb5 in spine development. This project will determine the expression pattern of Creb5 during spine development stage and adult stage; will delineate the fate of Creb5-expressing cells during spine development; and test whether Creb5HA-CreERt2 mice can be an adult stage genetic tool with temporal control to target all mature annulus fibrosus cells. This project will also identify both Creb5 regulated genes and chromatin regulatory elements that bind Creb5 in the intervertebral disc.