Graham Dianca R, Overbeek Paul A, Ash John D
Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, 73104, USA.
Invest Ophthalmol Vis Sci. 2005 Jul;46(7):2601-10. doi: 10.1167/iovs.05-0129.
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.
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.
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.
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.
gp130的激活配体，包括白血病抑制因子（LIF），可阻断视网膜神经元的分化和功能。本研究着重于确定LIF在体内是通过改变细胞命运还是通过阻断关键转录因子的表达来抑制光感受器的分化。
构建了在晶状体中特异性表达分泌型人LIF蛋白的转基因小鼠。通过组织学以及基因表达分析（采用原位杂交、免疫组织化学和实时定量逆转录PCR）评估视网膜分化。使用视网膜电图评估视网膜功能。
LIF并未阻止或改变外核层和内核层分离的时间，但它抑制了视杆细胞和视锥细胞中光转导基因的表达，从而阻断了光感受器的功能成熟。LIF还降低了Crx、Nrl和Nr2e3的表达，并上调了转录抑制因子Baf和Fiz1的表达。
LIF的表达似乎并未改变光感受器细胞命运的决定，但它抑制了随后的分化。这些结果表明，gp130配体可通过减少Crx和Nrl依赖的转录来抑制光感受器的功能分化。
