Liu Shuting, Chen Junyao, Chen Haiqiao, Guo Yanan, Yuan Fa, Xiao Dongchang, Xiang Mengqing
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Sun Yat-sen University, Guangzhou 510060, China.
Guangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
Proc Natl Acad Sci U S A. 2025 Jul 22;122(29):e2500871122. doi: 10.1073/pnas.2500871122. Epub 2025 Jul 15.
The retinal photoreceptors possess specialized sensory cilia critical for phototransduction while the nonphotoreceptor cells typically exhibit simpler primary cilia or lack them altogether. This dichotomy in ciliary architecture underpins the functional specialization of retinal cell types, but how this dichotomy arises and is maintained remains elusive. This study explores the role of the transcription factor Foxn3 in establishing and maintaining this divergence. We generated retina-specific conditional knockout (Foxn3CKO) mice, which show that Foxn3 is essential for repressing ciliary gene expression in nonphotoreceptor cells, such as bipolar and amacrine cells. Foxn3CKO mice exhibit significant reductions in electroretinogram b-wave amplitudes and oscillatory potentials, indicating functional impairments in inner retinal neurons. Loss of leads to ectopic ciliary gene expression and abnormal ciliogenesis in nonphotoreceptor neurons, without affecting retinal cell specification and differentiation. Single-Cell RNA Sequencing, chromatin profiling, and transcription assays reveal that Foxn3 directly binds to and represses the promoters of ciliary genes and their transactivators, including and family members. Our data together highlight Foxn3 as a key transcriptional repressor that may function to ensure the proper ciliary architecture of retinal neurons by preventing nonphotoreceptor neurons from adopting photoreceptor-like ciliary features and provide insights into the molecular mechanisms governing retinal development and ciliopathies.
视网膜光感受器拥有对光转导至关重要的特化感觉纤毛，而非光感受器细胞通常表现出更简单的初级纤毛或完全没有纤毛。纤毛结构的这种二分法是视网膜细胞类型功能特化的基础，但这种二分法如何产生和维持仍然不清楚。本研究探讨了转录因子Foxn3在建立和维持这种差异中的作用。我们生成了视网膜特异性条件性敲除（Foxn3CKO）小鼠，结果表明Foxn3对于抑制非光感受器细胞（如双极细胞和无长突细胞）中的纤毛基因表达至关重要。Foxn3CKO小鼠的视网膜电图b波振幅和振荡电位显著降低，表明视网膜内层神经元存在功能障碍。Foxn3的缺失导致非光感受器神经元中纤毛基因的异位表达和异常纤毛发生，而不影响视网膜细胞的特化和分化。单细胞RNA测序、染色质分析和转录分析表明，Foxn3直接结合并抑制纤毛基因及其转录激活因子的启动子，包括 和 家族成员。我们的数据共同表明，Foxn3作为一种关键的转录抑制因子，可能通过防止非光感受器神经元呈现光感受器样纤毛特征来确保视网膜神经元的正确纤毛结构，并为控制视网膜发育和纤毛病的分子机制提供了见解。
