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

• Published in: Nature genetics Vol. 25; no. 4; pp. 453 - 457
• Main Authors: Matzuk, Martin M, Brown, Chester W, Houston-Hawkins, Dianne E, Woodruff, Teresa K
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 01-08-2000
• Subjects: activin; Activins; Alleles; Animals; Biological and medical sciences; Body Weight; Cell differentiation, maturation, development, hematopoiesis; Cell physiology; Cells, Cultured; CHO Cells; Compensation; Cricetinae; DNA, Recombinant; Embryo, Mammalian - metabolism; Female; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Developmental; Genetic aspects; Genotype; Hair; Hybridization; In Situ Hybridization; Inhba gene; Inhbb gene; Inhibin-beta Subunits; Inhibins - genetics; Inhibins - physiology; Male; Mice; Mice, Inbred Strains; Mice, Mutant Strains; Molecular and cellular biology; Multifactorial traits; Mutagenesis, Insertional; Mutation; Neurosciences; Oligopeptides; Organ Size; Ovaries; Ovary - metabolism; Peptides; Peptides - genetics; Phenotype; Physiological aspects; Pregnancy; Proteins; RNA - genetics; RNA - metabolism; Stem cells; Survival Analysis; Testes; Testis - growth & development; Testis - metabolism; Transforming growth factors; United States > US; Vertebrata; Phenotype; Mammalia; Mouse; Transforming growth factor β; Rodentia; Transgenic animal; Development; Multigene family; Mutation; Activin; Gene expression
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/78161

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 development. Whereas mice homozygous for the Inhba-null allele demonstrate disruption of whisker, palate and tooth development, leading to neonatal lethality, homozygous Inhbb-null mice are viable, fertile and have eye defects. 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.