Roles Of Vps18 In Purkinje Cell Development And Lung Tumorigenesis

Lysosomes play vital roles in multiple pathways, like pathogen defense, nutrients uptake, organelle recirculation and signaling transduction. Many diseases are relating to lysosome dysfunction, including Alzheimer Disease and Glycogen Storage Disease. Vps18 (Vacuolar Protein Sorting 18) is one of the four subunits of Class C Vps Complex, which plays crucial roles in lysosome formation. Our previous research showed that conditional knock-out (CKO) of Vps18 gene in mouse neuronal cells would cause massive apoptosis of neurons and block the migration of neural progenitor cells, which lead to the death of neonatal mice within 12 days after birth. Besides, the development of cerebellar Purkinje cells was also impaired. However, the early death of pups impeded the research of Vps18’s function in postnatal neural development and behavior. Here we report that mice with conditional knock-out (CKO) of Vps18 gene in cerebellar Purkinje cells are viable and fertile, but with severe behavior disability phenotype similar to cerebellar ataxia. However, the Purkinje dendrites show normal development in adult Vps18 deficient mice, despite the loss of most Purkinje cells. This indicates that Vps18 may only execute its function during the early stage of Purkinje cell development, but not the later one. Moreover, Lox protein is found deposited in Vps18 mutated cerebellum, which may contribute to the death of Purkinje cells. Our research manifests the vital function of Vps18 gene in cerebellum Purkinje cells, which may provide novel clues and proofs for neurodegenerative diseases research, especially for cerebellar ataxia disease.Lysosome plays crucial physiological roles in eukaryotic species. However, its function in tumorigenesis is largely unknown. Here we report that the conditional loss of Vps18, an indispensable gene for lysosome maturation, would lead to enhanced lung tumorigenesis in LSL-K-rasG12D mice. An increased number and proportion of lung tumor foci are observed in Vps18 conditional knockout mice, comparing to the control group. TUNEL assay and western blot of Caspase3 revealed that the apoptosis status of tumor cells was not affected by Vps18 depletion. However, enhanced cell proliferation in Vps18 knockout lung tumor foci were observed by EdU incorporation. Moreover, western blots of tumor foci samples showed that EGFR was accumulated in Vps18 knockout lung tumor foci, as well as the phosphorylated Stat3 transcription factor, which is the downstream component of EGFR. Our research revealed the important function of Vps18 gene in lung tumorigenesis, which may facilitate the understanding of lysosome function in cancer.