Abstract
Transport of newly synthesized proteins from the endoplasmic reticulum (ER) to the Golgi is mediated by the coat protein complex COPII. The inner coat of COPII is assembled from heterodimers of SEC23 and SEC24. Though mice with mutations in one of the four Sec24 paralogs, Sec24b, exhibit a neural tube closure defect, deficiency in humans or mice has not yet been described for any of the other Sec24 paralogs. We now report characterization of mice with targeted disruption of Sec24d. Early embryonic lethality is observed in mice completely deficient in SEC24D, while a hypomorphic Sec24d allele permits survival to mid-embryogenesis. Mice haploinsufficient for Sec24d exhibit no phenotypic abnormality. A BAC transgene containing Sec24d rescues the embryonic lethality observed in Sec24d-null mice. These results demonstrate an absolute requirement for SEC24D expression in early mammalian development that is not compensated by the other three Sec24 paralogs. The early embryonic lethality resulting from loss of SEC24D in mice contrasts with the previously reported mild skeletal phenotype of SEC24D deficiency in zebrafish and restricted neural tube phenotype of SEC24B deficiency in mice. Taken together, these observations suggest that the multiple Sec24 paralogs have developed distinct functions over the course of vertebrate evolution.
Highlights
One-third of all vertebrate proteins traverse the intracellular secretory pathway prior to being secreted into the extracellular space or transported to any of a number of intracellular compartments, including the Golgi, endosome, lysosome, or plasma membrane [1,2,3]
SEC24D is Required for Early Embryonic Development in the Mouse Genomic PCR and sequencing identified the Sec24dgt gene trap insertion site at position 3378 of intron 8, numbering from the start of the intron (GenBank accession number KC763189) (Figures 1A,B, 4A–C)
Of 209 pups genotyped at weaning, no Sec24dgt/gt mice were observed (p,7610217)
Summary
One-third of all vertebrate proteins traverse the intracellular secretory pathway prior to being secreted into the extracellular space or transported to any of a number of intracellular compartments, including the Golgi, endosome, lysosome, or plasma membrane [1,2,3]. Following co-translational translocation into the endoplasmic reticulum (ER) lumen, newly synthesized proteins are folded and undergo initial post-translational modification, followed by exit from the ER at ribosome-free regions called ER exit sites (ERES) [4] via COPII-coated vesicles [1,5,6]. The COPII coat is composed of the small GTPbinding protein Sar1p, the heterodimeric Sec23p/Sec24p complex and the heterotetrameric Sec13p/Sec31p complex [7]. Sar1p generates membrane curvature and initiates vesicle formation by inserting an N-terminal amphipathic helix into the ER membrane [8]. The active membrane-bound Sar1p-GTP recruits Sec23p/ Sec24p, and Sec24p drives the selective recruitment of cargo proteins into budding vesicles [9,10,11]. Polymerization of the outer Sec13p/Sec31p complex is the final step in vesicle budding [12]
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