STAT3-mediated signaling in the determination of rod photoreceptor cell fate in mouse retina.
OBJECTIVE
The purpose of this study was to determine the intracellular pathways by which ciliary neurotrophic factor (CNTF) and leukemia inhibitory factor (LIF) negatively regulate the development of rod photoreceptors in the mouse retina.


METHODS
Retina explant cultures derived from timed-pregnant CD-1 mice were used to monitor rod photoreceptor differentiation. CNTF was used to activate the signal transducer and activator of transcription (STAT)-3 and mitogen-activated protein kinase (MAPK) signal transduction pathways. Activation of STAT3 and MAPK were manipulated by using dominant-negative STAT3 recombinant adenoviruses and a specific inhibitor of MAPK, respectively. Explanted retinas were harvested at distinct time points and processed for immunohistochemistry.


RESULTS
Blocking of the MAPK pathway by the MAPK inhibitor PD98059 did not affect normal development of rods in retina explants or the suppression of their appearance by treatment with CNTF. In contrast, activated STAT3 was necessary for suppression of the rod cell fate decision. A deficiency of the STAT3 pathway induced by a dominant negative STAT3 abolished inhibition of rod development by CNTF.


CONCLUSIONS
These results indicate that STAT3, but not MAPK, can critically regulate photoreceptor development during mouse retina development.
Zhang
Samuel Shao-Min
SS
Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Wei
Jiye
J
Qin
Hua
H
Zhang
Lixin
L
Xie
Bing
B
Hui
Pei
P
Deisseroth
Albert
A
Barnstable
Colin J
CJ
Fu
Xin-Yuan
XY
D000818:Animals; D015153:Blotting, Western; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D020934:Ciliary Neurotrophic Factor / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D019084:Fluorescent Antibody Technique, Indirect; D007124:Immunoenzyme Techniques; D015850:Interleukin-6 / Q000494:pharmacology; D053605:Leukemia Inhibitory Factor; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011247:Pregnancy; D012160:Retina / Q000196:embryology*; D017948:Retinal Rod Photoreceptor Cells / Q000166:cytology* / Q000378:metabolism; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects*; D015534:Trans-Activators / Q000378:metabolism*
D020934:Ciliary Neurotrophic Factor; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D005419:Flavonoids; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one