Induction of the ganglion cell differentiation program in human retinal progenitors before cell cycle exit

Abstract

Despite the disease relevance, understanding of human retinal development lags behind that of other species. We compared the kinetics of gene silencing or induction during ganglion cell development in human and murine retina. Induction of POU4F2 (BRN3B) marks ganglion cell commitment, and we detected this factor in S-phase progenitors that had already silenced Cyclin D1 and VSX2 (CHX10). This feature was conserved in human and mouse retina, and the fraction of Pou4f2+ murine progenitors labeled with a 30 min pulse of BrdU matched the fraction of ganglion cells predicted to be born in a half-hour period. Additional analysis of 18 markers revealed many with conserved kinetics, such as the POU4F2 pattern above, as well as the surprising maintenance of "cell cycle" proteins KI67, PCNA, and MCM6 well after terminal mitosis. However, four proteins (TUBB3, MTAP1B, UCHL1, and RBFOX3) showed considerably delayed induction in human relative to mouse retina, and two proteins (ISL1, CALB2) showed opposite kinetics, appearing on either side of terminal mitosis depending on the species. With some notable exceptions, human and murine ganglion cell differentiation show similar kinetics, and the data add weight to prior studies supporting the existence of biased ganglion cell progenitors.