Connective Tissue Growth Factor: An Important Extracellular Cue in Retinal Progenitor Cell Growth and Differentiation

Abstract

The mouse retina is an established model for investigating the mechanisms of progenitor cell proliferation and cell fate specification. During development, multipotent retinal progenitor cells (RPC) give rise to seven major classes of retinal cell types that organize into three layers. The outer nuclear layer contains the cell bodies of the light-sensing rod and cone photoreceptors. The inner nuclear layer contains the cell bodies of various interneurons and Müller glia. Finally, the ganglion cell layer contains retinal ganglion cells (RGCs), which send their axons to the brain. Major efforts have been deployed to develop stem cell-based therapies to replace lost or deficient retinal cells causing blindness. However, transplantation of multipotent RPC or mature cells into the adult retina did not achieve significant integration. Although extracellular matrix (ECM) proteins play significant roles in adhesion, migration, proliferation, and, differentiation, their role in RPC differentiation and lineage specification is unknown. This study focuses on the connective tissue growth factor (CTGF), a multimodular ECM protein involved in different cellular and biological events. This thesis work seeks to examine the role of this protein in retinogenesis using lineage tracing and mouse genetics. Aim 1 will focus on the expression and cellular localization of CTGF during retinal development aided by a green fluorescent protein (GFP) transgenic mouse under the CTGF promoter control, a proxy for endogenous CTGF expression. Aim 2 will determine the effects of the absence of CTGF on retinogenesis during early embryonic stage using Cre-LoxP based deletion of the gene. Aim 3 will investigate the effect of CTGF in the ex-vivo systems to provide the proof of concept. Overall, these studies will essentially advance our current understanding the role of CTGF in retinal progenitor cell differentiation and lineage specification.