Translocon‐associated protein subunit Trap‐γ/Ssr3 is required for vascular network formation in the mouse placenta

Abstract

The translocon-associated protein (TRAP, also termed the signal sequence receptor) complex is required for the efficient translocation of secretory and membrane proteins in the endoplasmic reticulum, and is also involved in the endoplasmic reticulum stress-mediated unfolded protein response pathway. To investigate the roles of Trap-g, a TRAP complex subunit, we generated Trap-g knockout mice and found that mutant pups died soon after birth because of retarded embryonic organ growth, especially in the lung. The mutant placentae showed severe vascular network malformation in the labyrinth and significant reductions in blood space areas, which had an adverse effect on intrauterine embryonic growth. Placental malformation was already found by the mid-gestation-stage mutant placenta, with poor vascular endothelial cell proliferation in the chorionic plate region and increased apoptotic cell death in the labyrinth. Thus, Trap-g appears to be required for vascular network formation in murine placental development. Developmental Dynamics 240:394-403,

Mutations in the translocon‐associated protein complex subunit SSR3 cause a novel congenital disorder of glycosylation

“…For example, we had previously reported that pathogenic variants in the TRAP complex subunit, SSR4 , causes a CDG characterized by developmental and intellectual delays with varying system involvements . Yet, only one mouse model has been generated for studying the developmental role of either the OST or TRAP complex and it involved Ssr3 …”

“…The individual we report herein, also had severe respiratory distress at birth. When compared to wild‐type litter mates, placenta from Ssr3 KO mice are smaller in total size, but also had widespread vascular network malformations which could explain the IUGR . It is unclear if CDG‐0359 had placenta abnormalities.…”

“…14,20 Yet, only one mouse model has been generated for studying the developmental role of either the OST or TRAP complex and it involved Ssr3. 22 Ssr3 knockout (KO) mice display severe intrauterine embryonic growth retardation (IUGR) and die shortly after birth, possibly from severe organ growth deficiency that is especially prominent in the lungs. The individual we report herein, also had severe respiratory distress at birth.…”

Dullard/Ctdnep1 Modulates WNT Signalling Activity for the Formation of Primordial Germ Cells in the Mouse Embryo

“…Procedures for whole mount and section in situ hybridization, immunostaining, detection of alkaline phosphatase (AP) activity, and detection of β-galactosidase activity by X-gal staining have been described elsewhere [19], [20]. A cDNA fragment of Dullard (775 bp) spanning the open reading frame was used as the riboprobe.…”

Membrane insertion and topology of the translocon-associated protein (TRAP) gamma subunit

“…Most of these studies have been carried out using in vitro reconstituted systems, mainly with microsomal membranes. Its role in membrane protein biogenesis has been emphasised in vivo, where it has been shown that TRAP-α subunit mutant alters mammalian heart development [13], a mutation in TRAP-δ has been related to human congenital disorders of glycosylation [14], and TRAP-γ subunit plays an important role in the process of pronephros differentiation during Xenopus development [15], and appears to be required for vascular network formation in murine placental development [16]. Despite the general importance of the TRAP complex in secreted and membrane protein biogenesis, and the particular involvement of TRAP-γ subunit in development, its membrane topology has not been thoroughly investigated.…”