title: Ablation of vacuole protein sorting 18 (Vps18) gene leads to neurodegeneration and impaired neuronal migration by disrupting multiple vesicle transport pathways to lysosomes.
abstract: Intracellular vesicle transport pathways are critical for neuronal survival and central nervous system development. The Vps-C complex regulates multiple vesicle transport pathways to the lysosome in lower organisms. However, little is known regarding its physiological function in mammals. We deleted Vps18, a central member of Vps-C core complex, in neural cells by generating Vps18(F/F); Nestin-Cre mice (Vps18 conditional knock-out mice). These mice displayed severe neurodegeneration and neuronal migration defects. Mechanistic studies revealed that Vps18 deficiency caused neurodegeneration by blocking multiple vesicle transport pathways to the lysosome, including autophagy, endocytosis, and biosynthetic pathways. Our study also showed that ablation of Vps18 resulted in up-regulation of β1 integrin in mouse brain probably due to lysosome dysfunction but had no effects on the reelin pathway, expression of N-cadherin, or activation of JNK, which are implicated in the regulation of neuronal migration. Finally, we demonstrated that knocking down β1 integrin partially rescued the migration defects, suggesting that Vps18 deficiency-mediated up-regulation of β1 integrin may contribute to the defect of neuronal migration in the Vps18-deficient brain. Our results demonstrate important roles of Vps18 in neuron survival and migration, which are disrupted in multiple neural disorders.
authors.affiliation: Institute of Developmental Biology and Molecular Medicine, Fudan University, Shanghai 200433, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Peng
authors.forename: Jian
authors.initials: J
authors.lastname: Ye
authors.forename: Shunfei
authors.initials: S
authors.lastname: Yan
authors.forename: Shanshan
authors.initials: S
authors.lastname: Kong
authors.forename: Ye
authors.initials: Y
authors.lastname: Shen
authors.forename: Chenyu
authors.initials: C
authors.lastname: Li
authors.forename: Qinyu
authors.initials: Q
authors.lastname: Li
authors.forename: Yufang
authors.initials: Y
authors.lastname: Zheng
authors.forename: Kejing
authors.initials: K
authors.lastname: Deng
authors.forename: Tian
authors.initials: T
authors.lastname: Xu
authors.forename: Wufan
authors.initials: W
authors.lastname: Tao
mesh_terms: D000818:Animals; D001693:Biological Transport, Active / Q000235:genetics; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement; D005786:Gene Expression Regulation / Q000235:genetics; D019012:Integrin beta1 / Q000096:biosynthesis / Q000235:genetics; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D000091042:Reelin Protein; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D015820:Cadherins; D019012:Integrin beta1; D009419:Nerve Tissue Proteins; D000091042:Reelin Protein; D033921:Vesicular Transport Proteins; C575743:Vps18 protein, mouse; C000717128:Reln protein, mouse