Kim Soo-Young, Park Christine Haewon, Moon Bo-Hyun, Seabold Gail K
Neurobiology-Neurodegeneration and Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA.
Life (Basel). 2024 Sep 2;14(9):1103. doi: 10.3390/life14091103.
Photoreceptors in the mammalian retina convert light signals into electrical and molecular signals through phototransduction and transfer the visual inputs to second-order neurons via specialized ribbon synapses. Two kinds of photoreceptors, rods and cones, possess distinct morphology and function. Currently, we have limited knowledge about rod versus (vs.) cone synapse development and the associated genes. The transcription factor neural retina leucine zipper (NRL) determines the rod vs. cone photoreceptor cell fate and is critical for rod differentiation. knockout mice fail to form rods, generating all cone or S-cone-like (SCL) photoreceptors in the retina, whereas ectopic expression of using a cone-rod homeobox () promoter (p) forms all rods. Here, we examined rod and cone pre-synapse development, including axonal elongation, terminal shaping, and synaptic lamination in the outer plexiform layer (OPL) in the presence or absence of . We show that NRL loss and knockdown result in delayed OPL maturation and plasticity with aberrant dendrites of bipolar neurons. The integrated analyses of the transcriptome in developing rods and SCLs with NRL CUT&RUN and synaptic gene ontology analyses identified G protein subunit beta () 1 and p21 (RAC1) activated kinase 5 () transcripts were upregulated in developing rods and down-regulated in developing SCLs. Notably, and are rod dominant, and is enriched in cones. NRL binds to the genes of , , and . NRL also regulates pre-synapse ribbon genes, and their expression is altered in rods and SCLs. Our study of histological and gene analyses provides new insights into the morphogenesis of photoreceptor pre-synapse development and regulation of associated genes in the developing retina.
哺乳动物视网膜中的光感受器通过光转导将光信号转换为电信号和分子信号，并通过特殊的带状突触将视觉输入传递给二级神经元。视杆细胞和视锥细胞这两种光感受器具有不同的形态和功能。目前，我们对视杆细胞与视锥细胞突触发育及相关基因的了解有限。转录因子神经视网膜亮氨酸拉链（NRL）决定视杆细胞与视锥细胞光感受器的细胞命运，对视杆细胞分化至关重要。NRL基因敲除小鼠无法形成视杆细胞，视网膜中生成的全是视锥细胞或类S视锥细胞（SCL）光感受器，而利用视锥-视杆同源框（CRX）启动子（p）异位表达NRL则会形成全是视杆细胞的情况。在此，我们研究了在有或没有NRL的情况下，视杆细胞和视锥细胞突触前发育，包括轴突伸长、终末塑形以及外网状层（OPL）中的突触分层。我们发现，NRL缺失和敲低会导致OPL成熟和可塑性延迟，同时双极神经元的树突出现异常。通过对发育中的视杆细胞和SCL进行NRL染色质切割与RUN分析（CUT&RUN）以及突触基因本体分析的转录组综合分析，确定G蛋白亚基β1（Gβ1）和p21（RAC1）激活激酶5（PAK5）转录本在发育中的视杆细胞中上调，而在发育中的SCL中下调。值得注意的是，Gβ1和PAK5在视杆细胞中占主导，而RAC1在视锥细胞中富集。NRL与Gβ1、PAK5和RAC1的基因结合。NRL还调节突触前带状基因，其在视杆细胞和SCL中的表达发生改变。我们的组织学和基因分析研究为视网膜发育过程中光感受器突触前发育的形态发生及相关基因的调控提供了新见解。
