Ciliary Neurotrophic Factor Promotes Müller Glia Differentiation from the Postnatal Retinal Progenitor Pool

Abstract

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 Müller glia genesis in the postnatal mouse retina. In both retinal monolayer and explant cultures, CNTF increases the number of progenitor cells adopting the Müller 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 Müller cells. In addition, increased levels of endogenous STAT3 and ERK phosphorylation have been observed at around postnatal day 5, coinciding with the peak of Müller 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 Müller cell production. Moreover, absorbing epidermal growth factor (EGF) signals with a neutralizing antibody did not affect CNTF-induced Müller glial genesis, indicating that the effect of CNTF is not mediated by the known Müller-enhancing activity of EGF. Together, these results support a novel function of CNTF-like cytokines in retinal gliogenesis.

Meteorin promotes the formation of GFAP-positive glia via activation of the Jak-STAT3 pathway

“…Moreover, we observed an increase in meteorin expression in CNTF-treated retinal explants, which induced Müller glia activation (supplementary material Fig. S3), confirming previous findings (Goureau et al, 2004). This result suggests that meteorin is upregulated in activated Müller cells.…”

“…6). These results also seem similar to the effect of CNTF on Müller glia (Goureau et al, 2004), which demonstrated that CNTF increases GFAP expression of Müller glia in P0 mouse retinal explant cultures, and at the same time, it increases the CRALBP-positive Müller glia cell population itself, indicating that CNTF is involved in differentiation of retinal precursor cells into Müller glia. However, we could not detect any change in Müller glial cell number in cultured retina either by meteorin or CNTF treatment.…”

“…Retinal neurons are generated from retinal precursor cells, from which Müller glia are also generated. As several previous reports have demonstrated, the mechanisms neuro-and gliogenesis in the retina and the brain are similar; for example, CNTF influences either retinal astrocyte differentiation or glial fate determination of retinal precursor cells (Goureau et al, 2004). These facts led us to hypothesize that meteorin has additional functions in retinal glia development.…”

“…Moreover, cytokine pathways that participate in brain astrogliogenesis function similarly in retinal glia development. For example, CNTF has been reported to promote Müller glia differentiation of retinal precursor cells with an increase in GFAP expression (Bhattacharya et al, 2008;Goureau et al, 2004).…”

Cytokine-Induced Activation of Signal Transducer and Activator of Transcription in Photoreceptor Precursors Regulates Rod Differentiation in the Developing Mouse Retina

“…As a consequence of STAT activation, nascent photoreceptor cells may accumulate cytokine signaling inhibitors and thus become resistant to environmental cytokine as well as other STAT-activating signals to reach maturation and sustain their physiological function. Concomitantly, postmitotic Müller glia may require cytokine and other growth factor signaling to further differentiate and form the glial scaffold necessary for retinal structure and maintenance (Lillien, 1995;Lillien and Wancio, 1998;Goureau et al, 2004). The integration of intracellular signaling events triggered by various cell-extrinsic cues in progenitor cells and postmitotic cells may thus contribute to a balanced production of postnatal cell types and their proper differentiation.…”