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


The activins (dimers of βA or βB subunits, encoded by the genes Inhba and Inhbb, respectively) are TGF-β superfamily members that have roles in reproduction and development1,2,3. Whereas mice homozygous for the Inhba-null allele demonstrate disruption of whisker, palate and tooth development, leading to neonatal lethality4,5, homozygous Inhbb-null mice are viable, fertile and have eye defects6,7. To determine if these phenotypes were due to spatiotemporal expression differences of the ligands or disruption of specific ligand-receptor interactions, we replaced the region of Inhba encoding the mature protein with Inhbb, creating the allele Inhbatm2Zuk (hereafter designated InhbaBK). Although the craniofacial phenotypes of the Inhba-null mutation were rescued by the InhbaBK allele, somatic, testicular, genital and hair growth were grossly affected and influenced by the dosage and bioactivity of the allele. Thus, functional compensation within the TGF-β superfamily can occur if the replacement gene is expressed appropriately. The novel phenotypes in these mice further illustrate the usefulness of insertion strategies for defining protein function.

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Figure 1: Generation of InhbaBK mice.
Figure 2: In situ hybridization of mouse ovary and embryo sections with βA and βB probes.
Figure 3: RNase protection assay and western-blot analysis.
Figure 4: Phenotypic analysis of wild-type and mutant mice.
Figure 5: Growth characteristics, survival and serum analysis of wild-type and mutant mice.


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We thank T.R. Kumar for measuring FSH levels; A. Lau and D. DeKretser for discussions; Q. Guo, P. Wang and Y. Wang for technical assistance; and W. Vale and J. Vaughan for providing antibodies to activin βA and βB proteins. This work was supported in part by NIH grants HD32067 (to M.M.M.), HD01156, HD27823 (to C.W.B.) and HD35708 (to T.K.W.), and the Robert Wood Johnson Foundation.

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Correspondence to Martin M. Matzuk.

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Brown, C., Houston-Hawkins, D., Woodruff, T. et al. Insertion of Inhbb into the Inhba locus rescues the Inhba-null phenotype and reveals new activin functions. Nat Genet 25, 453–457 (2000).

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