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HGNC Approved Gene Symbol: INHBA
Cytogenetic location: 7p14.1 Genomic coordinates (GRCh38): 7:41,685,114-41,705,406 (from NCBI)
The activins, which are dimers of beta-A and/or beta-B subunits encoded by the genes INHBA and INHBB (147390), respectively, are TGF-beta (see 190180) superfamily members that have roles in reproduction and development (Brown et al., 2000).
From the culture fluid of a human transformed cell line (THB-1) stimulated by phorbol 12-myristate 13-acetate, Murata et al. (1988) isolated a protein that exhibited potent differentiation-inducing activity toward mouse Friend erythroleukemia cells and human K-562 cells. Designated erythroid differentiation factor (EDF), the protein is a homodimer with a molecular weight of 25,000. Surprisingly, the sequence of EDF mRNA was found to be identical to that of the beta-A subunit of inhibin. Southern blot analysis indicated that only 1 gene for EDF/inhibin beta-A exists in the human genome. The follicle-stimulating hormone (FSH)-releasing protein (FRP) subunit is likewise identical in structure to the beta-A subunit of inhibin. Lumpkin et al. (1987) purified from sheep hypothalamus a fraction (presumably a peptide) that had selective FSH-releasing properties. They demonstrated dissimilarity of the purified factor from luteinizing hormone-releasing hormone (152760).
In a report on nomenclature conventions, Burger et al. (1988) suggested that the 2 forms of the inhibin beta subunit be referred to as beta-A and beta-B (see 147390). The beta dimer of inhibin, which stimulates FSH secretion, should be called activin; the homodimer of the beta-A subunit is to be termed activin A and the heterodimer consisting of 1 beta-A and 1 beta-B subunit termed activin A-B.
Tanimoto et al. (1996) determined that the INHBA gene has 3 exons. Initiation of coding sequence occurs in exon 2.
Hashimoto et al. (1992) showed that activin A had a mitogenic effect on mouse osteoblastic cells and suppressed their alkaline phosphatase activity. Both mouse and human osteoblastic cell lines secreted follistatin (FST; 136470), which inhibited the activity of activin A. Northern blot analysis showed that retinoic acid treatment downregulated follistatin expression. Hashimoto et al. (1992) concluded that follistatin is a negative regulator of activin A.
Ferguson et al. (1998) showed that activin beta-A is expressed in presumptive tooth-germ mesenchyme and is thus a candidate for a signaling molecule in tooth development. Analysis of tooth development in activin beta-A mutant embryos showed that incisor and mandibular molar teeth failed to develop beyond the bud stage. Activin beta-A is thus an essential component of tooth development. Development of maxillary molars, however, is unaffected in the mutants. Using tissue recombination experiments, Ferguson et al. (1998) showed that activin is required in the mesenchyme prior to bud formation and that although activin signaling from mesenchyme to epithelium takes place, mutant epithelium retains its ability to support tooth development. Implantation of beads soaked in activin A into developing mandibles is able to completely rescue tooth development from embryonic day (E) 11.5 but not E12.5 or E13.5, confirming that activin is an early essential mesenchyme signal required before tooth bud formation. Normal development of maxillary molars in the absence of activin shows a position-specific role for this pathway in development of dentition. Functional redundancy with activin B (see INHBB, 147390) or other TGF-beta (see TGFB1; 190180) family members that bind to activin receptors cannot explain development of maxillary molars in the mutants since the activin-signaling pathway appears not to be active in these tooth germs.
Activin ligands act as growth and differentiation factors in many cells and tissues. Mellor et al. (2000) examined the localization of and dimerization among activin subunits. The results demonstrated that activin beta-C (see 601233) can form dimers with activin beta-A and beta-B in vitro, but not with the inhibin alpha subunit (147380). Using a specific antibody, activin beta-C protein was localized to human liver and prostate and colocalized with beta-A and beta-B subunits to specific cell types in benign and malignant prostate tissues. The capacity to form novel activin heterodimers (but not inhibin C) appears to reside in the human liver and prostate. The authors concluded that formation of activin AC or BC heterodimers may have significant implications in the regulation of levels and/or biologic activity of other activins in these tissues.
You and Kruse (2002) studied corneal myofibroblast differentiation and signal transduction induced by the transforming growth factor-beta (TGFB) family members activin A and bone morphogenetic protein-7 (BMP7; 112267). They found that activin A induced phosphorylation of SMAD2 (601366), and BMP7 induced SMAD1 (601595), both of which were inhibited by follistatin. Transfection with antisense SMAD2/SMAD3 (603109) prevented activin-induced expression and accumulation of alpha-smooth muscle actin. The authors concluded that TGFB proteins have different functions in the cornea. Activin A and TGFB1, but not BMP7, are regulators of keratocyte differentiation and might play a role during myofibroblast transdifferentiation. SMAD2/SMAD3 signal transduction appeared to be important in the regulation of muscle-specific genes.
Valderrama-Carvajal et al. (2002) studied the signaling pathway activated by inhibin and TGF-beta (TGFB1; 190180) during apoptosis in mouse and human hematopoietic cell lines. They determined that the downstream effectors include SMAD (see 601595) and SHIP (601582), a 5-prime inositol phosphatase. Activation of the SMAD pathway induced SHIP expression, resulting in intracellular changes in phospholipid pools and inhibited phosphorylation of protein kinase B (AKT1; 164730).
Harjunmaa et al. (2012) reported that mouse tooth complexity can be increased substantially by adjusting multiple signaling pathways simultaneously. Harjunmaa et al. (2012) cultured teeth in vitro and adjusted ectodysplasin (EDA; 300451), activin A, and sonic hedgehog (SHH; 600725) pathways, all of which are individually required for normal tooth development. The authors quantified tooth complexity using the number of cusps and a topographic measure of surface complexity, and found that whereas activation of EDA and activin A signaling and inhibition of SHH signaling individually cause subtle to moderate increases in complexity, cusp number is doubled when all 3 pathways are adjusted in unison. Furthermore, the increase in cusp number does not result from an increase in tooth size, but from an altered primary patterning phase of development. The combination of a lack of complex mutants, the paucity of natural variants with complex phenotypes, and their results of greatly increased dental complexity using multiple pathways, suggests that an increase may be inherently different from a decrease in phenotypic complexity.
Matzuk et al. (1995) generated mice with mutations either in activin beta-A or in both activin beta-A and activin beta-B. Activin beta-A-deficient mice developed to term but died within 24 hours of birth. They lacked whiskers and lower incisors and had defects in their secondary palates, including cleft palate, demonstrating that activin beta-A must have a role during craniofacial development. Mice lacking both activin subunits showed the defects in both individual mutants but no additional defects, indicating that there is no functional redundancy between these proteins during embryogenesis.
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, Brown et al. (2000) replaced the region of Inhba encoding the mature protein with Inhbb, creating the allele designated Inhba(BK). Although the craniofacial phenotypes of the Inhba-null mutation were rescued by the Inhba(BK) allele, somatic, testicular, genital, and hair growth were grossly affected and influenced by the dosage and bioactivity of the allele. Thus, Brown et al. (2000) concluded that functional compensation within the TGF-beta 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. The structural organization of the testes of adult Inhba(BK/BK) mice was normal; however, the differentiation of the seminiferous tubules of Inhba(BK/-) mice was delayed. The testicular volumes of both Inhba(BK/BK) and Inhba(BK/-) mice were less than those of controls, and the dosage of the Inhba(BK) allele correlated positively with testicular size. Inhba(+/BK) males had normal onset of fertility, whereas Inhba(BK/BK) males had delayed onset of fertility similar to Acvr2 (102581) -/- mice. Only 1 in 6 Inhba(BK/BK) females produced litters, whereas Inhba(+/BK) females were normally fertile. The ovaries of Inhba(BK/-) mice were smaller and contained fewer large preantral follicles than those of controls. Inhba(BK/BK) and Inhba(BK/-) mice were identified by their smaller size, slower hair growth, the rough appearance of their fur, and sunken eyes. Approximately 50% of Inhba(BK/BK) mice died by 26 weeks, whereas Inhba(BK/-) mice invariably became cachectic and died between 3 and 4 weeks. The summary of phenotypic findings of Inhba(BK/-) mice includes short whiskers, normal tooth development, no cleft palate, symmetric growth deficiency (severe), enlargement of external genitalia, hypogonadism (severe), delayed hair growth (moderate), hypoglycemia (mild), decreased life expectancy (severe), and anemia.
Jones et al. (2007) showed that lipopolysaccharide (LPS) challenge in mice resulted in a rapid increase in activin levels through activation of Tlr4 (603030) and Myd88 (602170). Treatment with the activin-binding protein Fst reduced Tnf (191160) and Il6 (147620) levels and increased Il1b (147720) levels after LPS stimulation. Administration of Fst to mice before challenge with a lethal dose of LPS significantly increased survival, and serum activin A levels were higher in mice that succumbed compared with those that survived. Jones et al. (2007) concluded that activin A has an important role in the inflammatory response and that FST may have significant therapeutic potential to reduce the severity of inflammatory diseases.
Archambeault and Yao (2010) found that conditional ablation of Inhba expression in fetal mouse Leydig cells resulted in testis cord dysgenesis due to decreased Sertoli cell proliferation, leading to abnormal testis histology by birth. Ablation of Smad4 (600993) recapitulated testis cord dysgenesis of Inhba -/- Leydig cells. Archambeault and Yao (2010) concluded that Inhba is the major TGF-beta protein expressed by fetal Leydig cells that acts directly upon Sertoli cells to promote their proliferation during late embryogenesis.
Archambeault, D. R., Yao, H. H.-C. Activin A, a product of fetal Leydig cells, is a unique paracrine regulator of Sertoli cell proliferation and fetal testis cord expansion. Proc. Nat. Acad. Sci. 107: 10526-10531, 2010. [PubMed: 20498064] [Full Text: https://doi.org/10.1073/pnas.1000318107]
Brown, C. W., Houston-Hawkins, D. E., Woodruff, T. K., Matzuk, M. M. Insertion of Inhbb into the Inhba locus rescues the Inhba-null phenotype and reveals new activin functions. Nature Genet. 25: 453-457, 2000. [PubMed: 10932194] [Full Text: https://doi.org/10.1038/78161]
Burger, H. G., Igarashi, M., Baird, D., Mason, T., Bardin, W., McLachlan, R., Chappel, S., Miyamoto, K., de Jong, F., Moudgal, A., Demoulin, A., Nieschlag, E., de Kretser, D., Robertson, D., Findlay, J., Sasamoto, S., Forage, R., Schwartz, N., Fukuda, M., Steinberger, A., Hasegawa, Y., Tanabe, K., Ling, N., Ying, S.-Y. Inhibin: definition and nomenclature, including related substances. (Letter) J. Clin. Endocr. Metab. 66: 885-886, 1988. [PubMed: 3346366]
Ferguson, C. A., Tucker, A. S., Christensen, L., Lau, A. L., Matzuk, M. M., Sharpe, P. T. Activin is an essential early mesenchymal signal in tooth development that is required for patterning of the murine dentition. Genes Dev. 12: 2636-2649, 1998. [PubMed: 9716414] [Full Text: https://doi.org/10.1101/gad.12.16.2636]
Harjunmaa, E., Kallonen, A., Voutilainen, M., Hamalainen, K., Mikkola, M. L., Jernvall, J. On the difficulty of increasing dental complexity. Nature 483: 324-327, 2012. [PubMed: 22398444] [Full Text: https://doi.org/10.1038/nature10876]
Hashimoto, M., Shoda, A., Inoue, S., Yamada, R., Kondo, T., Sakurai, T., Ueno, N., Muramatsu, M. Functional regulation of osteoblastic cells by the interaction of activin-A with follistatin. J. Biol. Chem. 267: 4999-5004, 1992. [PubMed: 1537876]
Jones, K. L., Mansell, A., Patella, S., Scott, B. J., Hedger, M. P., de Kretser, D. M., Phillips, D. J. Activin A is a critical component of the inflammatory response, and its binding protein, follistatin, reduces mortality in endotoxemia. Proc. Nat. Acad. Sci. 104: 16239-16244, 2007. [PubMed: 17911255] [Full Text: https://doi.org/10.1073/pnas.0705971104]
Lumpkin, M. D., Moltz, J. H., Yu, W. H., Samson, W. K., McCann, S. M. Purification of FSH-releasing factor: its dissimilarity from LHRH of mammalian, avian, and piscian origin. Brain Res. Bull. 18: 175-178, 1987. [PubMed: 3552127] [Full Text: https://doi.org/10.1016/0361-9230(87)90188-2]
Matzuk, M. M., Kumar, T. R., Vassalli, A., Bickenbach, J. R., Roop, D. R., Jaenisch, R., Bradley, A. Functional analysis of activins during mammalian development. Nature 374: 354-356, 1995. [PubMed: 7885473] [Full Text: https://doi.org/10.1038/374354a0]
Mellor, S. L., Cranfield, M., Ries, R., Pedersen, J., Cancilla, B., de Kretser, D., Groome, N. P., Mason, A. J., Risbridger, G. P. Localization of activin beta(A)-, beta(B)-, and beta(C)-subunits in human prostate and evidence for formation of new activin heterodimers of beta(C)-subunit. J. Clin. Endocr. Metab. 85: 4851-4858, 2000. [PubMed: 11134153] [Full Text: https://doi.org/10.1210/jcem.85.12.7052]
Murata, M., Eto, Y., Shibai, H., Sakai, M., Muramatsu, M. Erythroid differentiation factor is encoded by the same mRNA as that of the inhibin beta-A chain. Proc. Nat. Acad. Sci. 85: 2434-2438, 1988. [PubMed: 3267209] [Full Text: https://doi.org/10.1073/pnas.85.8.2434]
Tanimoto, K., Yoshida, E., Mita, S., Nibu, Y., Murakami, K., Fukamizu, A. Human activin beta-A gene: identification of novel 5-prime exon, functional promoter, and enhancers. J. Biol. Chem. 271: 32760-32769, 1996. [PubMed: 8955111] [Full Text: https://doi.org/10.1074/jbc.271.51.32760]
Valderrama-Carvajal, H., Cocolakis, E., Lacerte, A., Lee, E.-H., Krystal, G., Ali, S., Lebrun, J.-J. Activin/TGF-beta induce apoptosis through Smad-dependent expression of the lipid phosphatase SHIP. Nature Cell Biol. 4: 963-969, 2002. [PubMed: 12447389] [Full Text: https://doi.org/10.1038/ncb885]
You, L., Kruse, F. E. Differential effect of activin A and BMP-7 on myofibroblast differentiation and the role of the Smad signaling pathway. Invest. Ophthal. Vis. Sci. 43: 72-81, 2002. [PubMed: 11773015]