ABSTRACTThe COPII component SEC24 mediates the recruitment of transmembrane cargoes or cargo adaptors into newly forming COPII vesicles on the ER membrane. Mammalian genomes encode fourSec24paralogs (Sec24a-d), with two subfamilies based on sequence homology (SEC24A/B and C/D), though little is known about their comparative functions and cargo-specificities. Complete deficiency forSec24dresults in very early embryonic lethality in mice (before the 8 cell stage), with later embryonic lethality (E 7.5) observed inSec24cnull mice. To test the potential overlap in function between SEC24C/D, we employed dual recombinase mediated cassette exchange to generate aSec24cc-dallele, in which the C-terminal 90% of SEC24C has been replaced by SEC24D coding sequence. In contrast to the embryonic lethality at E7.5 of SEC24C-deficiency,Sec24cc-d/c-dpups survive to term, though dying shortly after birth.Sec24cc-d/c-dpups are smaller in size, but exhibit no obvious developmental abnormality. These results suggest that tissue-specific and/or stage-specific expression of theSec24c/dgenes rather than differences in cargo function explain the early embryonic requirements for SEC24C and SEC24D.