Ciliary neurotrophic factor promotes muller glia differentiation from the postnatal retinal progenitor pool

Ciliary neurotrophic factor (CNTF) exhibits multiple biological effects during vertebrate retinal development, including regulating the differentiation of photoreceptor cells and promoting the survival and axonal growth of ganglion cells. We report here that in addition to affecting the differentiation of retinal neurons, CNTF also promotes Muller glia genesis in the postnatal mouse retina. In both retinal monolayer and explant cultures, CNTF increases the number of progenitor cells adopting the Muller cell fate. Exogenous CNTF induces phosphorylation of signal transducers and activators of transcription (STAT)3 and extracellular signal-regulated kinase (ERK) among neonatal progenitor cells and newborn Muller cells. In addition, increased levels of endogenous STAT3 and ERK phosphorylation have been observed at around postnatal day 5, coinciding with the peak of Muller glia genesis. Perturbation of STAT and ERK signaling using protein kinase inhibitors and a dominant-negative STAT3 mutant demonstrates that both CNTF-induced STAT and ERK activation are involved in promoting Muller cell production. Moreover, absorbing epidermal growth factor (EGF) signals with a neutralizing antibody did not affect CNTF-induced Muller glial genesis, indicating that the effect of CNTF is not mediated by the known Muller-enhancing activity of EGF. Together, these results support a novel function of CNTF-like cytokines in retinal gliogenesis.