VPS4B deficiency causes early embryonic lethality and induces signal transduction disorders of cell endocytosis

Abstract

Summary VPS4B (vacuolar protein sorting 4B), a member of the ATPase associated with diverse cellular activities (AAA) protein family, is a component of the endosomal sorting complexes required for transport machinery which regulates the internalization and lysosomal degradation of membrane proteins. We previously reported that VPS4B is one of the pathogenic genes related to dentin dysplasia type I, although its function was largely unknown. To investigate the role of VPS4B in tooth development, we deleted the Vps4b gene in mice. We found that heterozygous knockout mice (Vps4b+/−) developed normally and were fertile. However, homozygous deletion of the Vps4b gene resulted in early embryonic lethality of Vps4b−/− mice at approximately embryonic day 9.5 (E9.5). To investigate the underlying molecular mechanisms, we examined the molecular functions of VPS4B in vivo and in vitro. Cell experiments showed that VPS4B influenced the proliferation, apoptosis, and cell cycle of transfected human neuroblastoma cells (IMR‐32 cells) with over‐expression or knockdown of VPS4B. Moreover, qRT‐PCR detection showed that the mRNA expression levels of apoptosis‐, cell cycle‐, and endocytosis‐related genes was significantly down or up‐regulated in RNA interference‐mediated knockdown of VPS4B in IMR‐32 cells and Vps4b+/− E12.5 embryos. We accordingly speculated that signal transduction disorders of cell endocytosis are a contributing factor to the prenatal lethality of Vps4b−/− mice.

Hereditary dentin defects with systemic diseases

“…VPS4B is a member of the ATPase associated with the diverse cellular activities (AAA) protein family. It is a component of the endosomal sorting complexes required for transport machinery, which regulates the internalization and lysosomal degradation of membrane proteins (Chen et al, 2021). VPS4B plays a vital role in dentin development by regulating the proliferation, migration, and differentiation of human dental pulp stem cells through the Wnt‐β‐catenin signaling pathway (Yang et al, 2016).…”