Cellular communication network (CCN) 2 is an extracellular matrix protein with cell type- and context-dependent functions. Using a combination of mouse genetics and omic approaches, we show that CCN2 is expressed in early embryonic retinal progenitor cells (RPCs) and becomes restricted to fully differentiated Muller glial cells (MGCs) thereafter. Germline deletion of CCN2 in mice decreases BrdU labeling, reduces RPC pool, and impairs the competency of remaining RPCs to generate early and late born retinal cell types. Retinal hypocellularity and microphthalmia ensue. The transcriptomic changes associated with CCN2 inactivation include reduced marker and transcriptional regulator genes of retinal ganglion cells, photoreceptors and MGCs. Yap (Yes-associated protein), a singular node for transcriptional regulation of growth and differentiation genes, is also a target of CCN2 signals. In an organotypic model of ex vivo cultured embryonic retinas, CCN2 and YAP immunoreactivity signals overlap. Lentivirus-mediated YAP expression in CCN2-deficient retinal explants increases the number of differentiating Sox9-positive MGCs. Taken together, our data indicate that CCN2 controls the proliferative and differentiation potentials of RPCs ultimately endowing, a subpopulation thereof, with Muller glial cell fate.