STAT3 activation in response to growth factors or cytokines participates in retina precursor proliferation.
Growth factors and cytokines play an important role in the development of central nervous systems including neurons of the retina. However, the molecular pathways that trigger cell growth remain unclear in neuronal precursors. In the present studies, we used a retinal explant culture system to investigate the response of signal transducer and activator of transcription factors (STATs) to extrinsic factors during mouse retinal development. Retinas from embryonic and neonatal stages showed that STAT3 but not STAT1 was activated in response to ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF), fibroblast growth factor-1 (FGF1), fibroblast growth factor-2 (FGF2), epidermal growth factor (EGF), interferon-alpha (IFN-alpha) and interferon-gamma (IFN-gamma) in distinct patterns. STAT3 activation was detected in the outermost retina layer in response to CNTF, LIF, FGF1, and IFN-alpha 24 hr after stimulation in postnatal day 1 (PN1) explants, but not FGF2, EGF, IFN-gamma, and retinoic acid (RA). Cytokine stimulation increased the number of cells incorporating BrdU and the labelled cells co-localized with phosphorylated STAT3, indicating that STAT3 may play an essential role in coupling extrinsic factors to retina precursor cell (RPC) proliferation. Furthermore, persistent expression of two neural precursor markers, Hes1 and Otx2 was detected in outer retinal layers and correlated with STAT3 activation by CNTF, suggesting that STAT3 activation may play a critical role in stimulating mitotic precursors. These results strongly support a model that STAT3-mediated signalling regulates precursor populations during mouse retina development.
Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Samuel Shao-Min
SS
Zhang
Mu-Gen
MG
Liu
Arihiro
A
Kano
Chun
C
Zhang
Xin-Yuan
XY
Fu
Colin J
CJ
Barnstable
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D049109:Cell Proliferation; D020934:Ciliary Neurotrophic Factor / Q000494:pharmacology; D016207:Cytokines / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D006133:Growth Substances / Q000494:pharmacology*; D018398:Homeodomain Proteins / Q000378:metabolism; D007091:Image Processing, Computer-Assisted / Q000379:methods; D051379:Mice; D008815:Mice, Inbred Strains; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D051857:Otx Transcription Factors; D012160:Retina / Q000187:drug effects / Q000196:embryology* / Q000378:metabolism; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000502:physiology; D046509:Tissue Culture Techniques; D015534:Trans-Activators / Q000378:metabolism*; D000072056:Transcription Factor HES-1
D051792:Basic Helix-Loop-Helix Proteins; D020934:Ciliary Neurotrophic Factor; D016207:Cytokines; D004268:DNA-Binding Proteins; D006133:Growth Substances; D018398:Homeodomain Proteins; D020928:Mitogen-Activated Protein Kinases; D051857:Otx Transcription Factors; D050796:STAT3 Transcription Factor; D015534:Trans-Activators; D000072056:Transcription Factor HES-1; C489734:Hes1 protein, mouse; C497660:Otx2 protein, mouse; C494087:Stat3 protein, mouse