Insertion of Inhbb into the Inhba locus rescues the Inhba-null phenotype and reveals new activin functions

The activins (dimers of beta A or beta B subunits, encoded by the genes Inh ba and Inhbb, respectively) are TGF-beta superfamily members that have role s in reproduction and devetopment(1-3). Whereas mice homozygous for the Inh ba-null allele demonstrate disruption of whisker, palate and tooth developm ent, leading to neonatal lethality(4,5), homozygous Inhbb-null mice are via ble, fertile and have eye defects(6,7). To determine if these phenotypes we re due to spatiotemporal expression differences of the ligands or disruptio n of specific ligand-receptor interactions, we replaced the region of Inhba encoding the mature protein with Inhbb, creating the allele Inhba(tm2Zuk) thereafter designated Inhba(BK)). Although the craniofacial phenotypes of t he Inhba-null mutation were rescued by the InhbaBK allele, somatic, testicu lar, genital and hair growth were grossly affected and influenced by the do sage and bioactivity of the allele. Thus, functional compensation within th e TGF-beta superfamily can occur if the replacement gene is expressed appro priately. The novel phenotypes in these mice further illustrate the usefuln ess of insertion strategies for defining protein function.