Regulation of retinal development and function by Cellular Communication Network Factor 2 (CCN2).

Abstract

During retinal development, multipotent retinal progenitor cells (RPCs) give rise to successive and overlapping waves of postmitotic neurons and Müller glia. The expression of specific transcription factors is well-known to direct cell fate specification from RPCs. However, the cell-extrinsic factors governing RPC differentiation are less understood. The extracellular matrix (ECM) protein Cellular Communication Network Factor 2 (CCN2), also known as Connective Tissue Growth Factor (CTGF), is a context-dependent mediator of angiogenesis, cytoskeletal remodeling, ECM stiffness, cell motility, proliferation, apoptosis, and adhesion. Recent studies suggest CCN2 is also a critical regulator of embryonic retinal development as well as the development of the retinal vasculature. Evidence further suggests retinogenesis is mediated by a Yes-associated protein (YAP)-CCN2 axis. However, the relevance of CCN2 and YAP-CCN2 regulation in postnatal retinal development and visual function are unclear. We aimed to address these questions by characterizing CCN2-dependent, retinal cell type-specific gene regulation and employing novel mouse models to interrogate CCN2 functions and the role of YAP-CCN2 regulation in the retina. By employing single-cell transcriptional profiling of CCN2-/- and CCN2+/+ embryonic retinas, we found CCN2 regulated ECM gene transcription in a cell type-dependent manner and facilitated retinal ganglion cell (RGC) specification. We also found retina-specific, mosaic CCN2 deletion permitted development of major retinal cell types and blood vessels yet resulted in selective loss of YAP expression by Müller glia and age-dependent visual dysfunction as measured by electroretinography. These findings indicate CCN2 is a critical regulator of RGC specification and implicate Müller glia-specific YAP-CCN2 regulation as essential for visual function.