Yu Zihua, Yan Jinhua, Liu Zhiming, Wang Haiyan, Luo Guanzheng, Chen Haiyang
MOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
West China Centre of Excellence for Pancreatitis and Laboratory of Stem Cell and Anti-Aging Research, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Front Cell Dev Biol. 2025 Jan 23;13:1508714. doi: 10.3389/fcell.2025.1508714. eCollection 2025.
CLN3 mutation causes Juvenile neuronal ceroid lipofuscinosis (JNCL, also known as Batten disease), an early onset neurodegenerative disorder. Patients who suffer from Batten disease often die at an early age. However, the mechanisms underlying how CLN3 loss develops Batten disease remain largely unclear. Here, using midgut system, we demonstrate that Cln3 has no effect on midgut homeostasis maintaince, including cellular component, intestinal stem cells (ISCs) proliferation and differentiation, but is necessary for ISC activation upon tissue damage. Cell type-specific Gal4 screening reveals that the failure of ISC activation during regeneration caused by Cln3 loss is ISC-autonomous. Through genetic analyses, we elucidate that JAK/STAT signaling in ISCs is not activated with Cln3 depletion upon tissue damage, and functions downstream of Cln3. Our study provides a potential mechanism underlying the development of CLN3-mediated Batten disease at cellular level.
CLN3基因突变会导致青少年神经元蜡样脂褐质沉积症（JNCL，也称为巴顿病），这是一种早发性神经退行性疾病。患有巴顿病的患者通常早年死亡。然而，CLN3缺失导致巴顿病的潜在机制在很大程度上仍不清楚。在这里，我们利用中肠系统证明，Cln3对中肠内环境稳态维持没有影响，包括细胞成分、肠道干细胞（ISC）增殖和分化，但在组织损伤时ISC激活是必需的。细胞类型特异性Gal4筛选显示，Cln3缺失导致再生过程中ISC激活失败是ISC自主性的。通过遗传分析，我们阐明，组织损伤时Cln3缺失不会激活ISC中的JAK/STAT信号，且该信号在Cln3下游发挥作用。我们的研究在细胞水平上提供了CLN3介导的巴顿病发生的潜在机制。
