State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, 510060, China; Department of Ophthalmology, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, 412000, China.
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, 510060, China; Biobank of Eye, State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510060, China.
Exp Eye Res. 2023 Aug;233:109524. doi: 10.1016/j.exer.2023.109524. Epub 2023 Jun 7.
Mitogen-activated protein kinase kinase kinase kinase-4 (MAP4K4) is a potential regulator of photoreceptor development. To investigate the mechanisms underlying MAP4K4 during the neuronal development of retinal photoreceptors, we generated knockout models of C57BL/6j mice in vivo and 661 W cells in vitro. Our findings revealed homozygous lethality and neural tube malformation in mice subjected to Map4k4 DNA ablation, providing evidence for the involvement of MAP4K4 in early stage embryonic neural formation. Furthermore, our study demonstrated that the ablation of Map4k4 DNA led to the vulnerability of photoreceptor neurites during induced neuronal development. By monitoring transcriptional and protein variations in mitogen-activated protein kinase (MAPK) signaling pathway-related factors, we discovered an imbalance in neurogenesis-related factors in Map4k4 -/- cells. Specifically, MAP4K4 promotes jun proto-oncogene (c-JUN) phosphorylation and recruits other factors related to nerve growth, ultimately leading to the robust formation of photoreceptor neurites. These data suggest that MAP4K4 plays a decisive role in regulating the fate of retinal photoreceptors through molecular modulation and contributes to our understanding of vision formation.
丝裂原活化蛋白激酶激酶激酶激酶 4（MAP4K4）是光感受器发育的潜在调节因子。为了研究 MAP4K4 在视网膜光感受器神经元发育中的作用机制，我们在体内和体外分别建立了 C57BL/6j 小鼠和 661W 细胞的基因敲除模型。我们的研究结果表明，Map4k4 DNA 缺失的小鼠出现纯合致死和神经管畸形，表明 MAP4K4 参与早期胚胎神经形成。此外，我们的研究表明，Map4k4 DNA 的缺失导致光感受器神经突在诱导性神经元发育过程中的脆弱性。通过监测丝裂原活化蛋白激酶（MAPK）信号通路相关因子的转录和蛋白变化，我们发现 Map4k4 -/- 细胞中的神经发生相关因子失衡。具体而言，MAP4K4 促进原癌基因 jun（c-JUN）的磷酸化，并募集与神经生长相关的其他因子，最终导致光感受器神经突的强烈形成。这些数据表明，MAP4K4 通过分子调节在调节视网膜光感受器的命运中起决定性作用，并有助于我们理解视觉形成。
