Leukemia inhibitory factor blocks expression of Crx and Nrl transcription factors to inhibit photoreceptor differentiation.
OBJECTIVE
Activating ligands of gp130, including leukemia inhibitory factor (LIF), can block differentiation and function of retinal neurons. This study focused on determining whether LIF inhibits differentiation of photoreceptors by altering cell fate or by blocking the expression of essential transcription factors in vivo.


METHODS
Transgenic mice were generated that had lens-specific expression of the secreted human LIF protein. Retinal differentiation was assessed by histology and by gene expression analysis, with in situ hybridization, immunohistochemistry, and real-time qRT-PCR. Electroretinograms were used to assess retinal function.


RESULTS
LIF did not prevent or alter the timing of outer and inner nuclear layer separation, but it inhibited phototransduction gene expression in both rods and cones, thereby blocking functional maturation of photoreceptors. LIF also reduced the expression of Crx, Nrl, and Nr2e3, and upregulated the expression of transcription inhibitors Baf and Fiz1.


CONCLUSIONS
LIF expression did not appear to alter photoreceptor cell fate specification, but it inhibited subsequent differentiation. These results suggest that gp130 ligands can inhibit photoreceptor functional differentiation by reducing Crx- and Nrl-dependent transcription.
Graham
Dianca R
DR
Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, 73104, USA.
Overbeek
Paul A
PA
Ash
John D
JD
D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000235:genetics*; D004596:Electroretinography; D004797:Enzyme-Linked Immunosorbent Assay; D005136:Eye Proteins / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D018398:Homeodomain Proteins / Q000235:genetics*; D017403:In Situ Hybridization; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007908:Lens, Crystalline / Q000378:metabolism; D053605:Leukemia Inhibitory Factor; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D057093:Orphan Nuclear Receptors; D020419:Photoreceptor Cells, Vertebrate / Q000473:pathology*; D011506:Proteins / Q000502:physiology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017299:Rod Opsins / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics*; D015854:Up-Regulation; D014785:Vision, Ocular / Q000235:genetics
D050976:Basic-Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D005136:Eye Proteins; C120694:Fiz1 protein, mouse; D018398:Homeodomain Proteins; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; C485736:Nr2e3 protein, mouse; C084884:Nrl protein, mouse; D057093:Orphan Nuclear Receptors; D011506:Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D017299:Rod Opsins; D015534:Trans-Activators; C109288:cone rod homeobox protein