Advisory Committee Chair
Rosa A Serra
Advisory Committee Members
Bradley K Yoder
Date of Award
Degree Name by School
Doctor of Philosophy (PhD) School of Medicine
The spinal column is composed of two components, the vertebra (VB) that provide support and the intervertebral disc (IVD) that provide weight distribution. The structural integrity of IVDs is maintained by a fibrocartilaginous tissue called the annulus fibrosus (AF) which can degenerate with age or trauma and contribute to chronic back pain. There are currently no diseases modifying treatments that curb IVD degeneration. Regenerative therapies to treat IVD degeneration can be developed from identifying the signaling factors required for AF differentiation, but these factors are unknown. Previously, we showed that TGFβ signaling is required for AF formation in mice and regulates IVD enriched genes. The aim of this research is to identify the pathways and downstream effectors that TGFβ signaling utilizes to stimulate the differentiation of spinal fibrous tissues, like AF, and to elucidate the role of TGFβ signaling on a process required for spinal column formation called resegmentation. To identify the pathways utilized by TGFβ signaling, sclerotomal tissue was isolated from E11.5 mouse embryos, and the expression of fibrous tissue differentiation markers, Scx, Adamtsl2, and Fmod, was measured in response to TGFβ1 treatment. My research shows that TGFβ, through ERK1/2, regulates the transcription factor Scx, which then acts in cooperation of Smad3 to regulate Adamtsl2 and Fibromodulin. These data established a novel pathway used by TGFβ signaling in the sclerotome. iv Next, I showed that TGFβ signaling is required for resegmentation. Lineage tracing dyes, DiD and DiO, were injected into the somites of E2.5 chick embryos with and without a TGFβ signaling inhibitor, SB431542. We determined resegmentation occurs by E6.5, and inhibition of TGFβ signaling disrupts resegmentation. Altered resegmentation is accompanied by spinal column defects such as VB and AF deformities. There was also a disruption in rostro caudal polarity in the sclerotome at E3.5 and myofiber differentiation defects. By identifying the role of TGFβ signaling in resegmentation and sclerotome differentiation, discoveries made from these studies can be used to treat congenital disorders resulting from resegmentation disruptions, such as Klippel Feil syndrome, and aid in drug discovery or tissue engineering strategies to regenerate damaged fibrous tissues.
Clayton, Sade Williams, "TGFβ Provides the Backbone of Embryogenesis: Elucidating the Role of TGFβ Signaling and its Downstream Effectors on Spinal Column Development" (2021). All ETDs from UAB. 617.