Dosage-dependent requirement of sedlin component of the TRAPP complex in mouse embryonic development

Abstract

Intracellular vesicle trafficking is essential for proper cellular function and mammalian development. Transport Protein Particle (TRAPP) complex regulates multiple vesicles transport pathways. Three TRAPP complexes have been identified in yeast with roles in ER-Golgi, post-Golgi transport and in autophagy. Sedlin (SEDL) is one of the subunit of the TRAPP complex and mutations in human SEDL gene are responsible for an X-linked recessive skeletal disorder called Spondyloepiphyseal Dysplasia Tarda (SEDT). The SEDL gene is ubiquitously expressed, however the underlying defect is only restricted to derangement of chondrogenesis reflecting the existence of another SEDL-related gene. We use gene-targeting and gene-trap mutagenesis strategies to investigate the functions of Sedl and Sedlp in mice. Our results show that Sedl (Sedlin) and Sedlp have redundant function and are essentially required for mouse development. We showed here that there is a dose-dependent requirement of Sedl and Sedlp in early embryonic development. Embryos with a reduced dosage of Sedl and Sedlp display a significantly reduced size with severe abnormalities and a disorganized yolk-sac endoderm structure. Electron microscopy study indicates morphological alterations of the intracellular compartments in compound mutant endoderm suggesting both Sedlin and Sedlp may be required for proper cellular trafficking. These results provide important insights into the functional roles of Sedlin components in mouse embryonic development.