Generation of activin receptor type IIB isoform-specific hypomorphic alleles

Activin receptor type IIB (Acvr2b) mediates multiple signals for transforming growth factor-β (TGF-β) family members, including Activin, Nodal, Bmp7, Gdf1, Gdf3, Myostatin (Gdf8), and Gdf11. Mouse Acvr2b gene generates four transcriptional isofomns (Acvr2b_1-4) via alternative splicing of two sequence domains located at the juxtaposition of the transmembrane domain. To investigate whether these splicing domains are essential for signal transduction of the Acvr2b receptor in vivo, we have generated a strain of mutant mice (Acvr2b^4/4) which produce only the Acvr2b₄ isoform, which lacks both splicing domains. Most homozygous Acvr2b^{4(neo)/4(neo)} mice, in which a neomycin-resistant cassette was inserted in Intron 4 displayed a mild form of anterior vertebral transformations. However, the penetrance of the vertebral defect was dramatically decreased when the neomycin-resistant cassette was deleted These results suggest that the Acvr2b₄ isoform is capable of compensating for the deficiency of the other three isofomns. In the absence of its subfamily receptor Acvr2a, however, the development of Acvr2b^4/4 mice was arrested at the gastrulation stage, recapitulating the Acvr2a^-/-; Acwr2b^+/- mutant phenotype. In this study, we demonstrate that this phenomenon is most likely due to the reduction in the expressed Acvr2b ₄ levels rather than to the functional deficiency of the Acvr2b ₄ isoform itself.