. 2016 Jul;8(7):a021881. doi: 10.1101/cshperspect.a021881

Table 2.

Mouse models of activin- and inhibin-related loss- and gain-of-function

Genotypes	Phenotypes	References
Loss-of-function/hypomorphic
Single-activin/inhibin mutants
Inhba^−/−	Failure to develop whiskers, incisors, mandibular molars; cleft palate (∼30%), neonatal lethality	Matzuk et al. 1995d
Inhba^−/−	Aberrant (absent) whisker development leads to secondary defects in whisker-associated trigeminal sensory function	Jhaveri et al. 1998
Inhba^−/−	Specific decrease in the number of retinal rod photoreceptors	Davis et al. 2000
Inhbb^−/−	Eyelid closure defect, prolonged gestation, impaired lactation, normal growth, gonadal differentiation, fertility, and survival; normal whisker and tooth development; no cleft palate	Schrewe et al. 1994; Vassalli et al. 1994
Inhba^BK/BK	Normal whisker and tooth development; no cleft palate; symmetrical growth deficiency (moderate), enlargement of external genitalia, hypogonadism (moderate), sunken eyes, short hair, delayed hair growth (mild), diminished female fertility, decreased life expectancy (mild/moderate), decreased white adipose (moderate), increased metabolic rate, mitochondrial dysfunction	Brown et al. 2000; Li et al. 2009
Inhba^BK/−	Short whiskers, normal tooth development; no cleft palate; symmetrical growth deficiency with reduced adiposity (severe), enlargement of external genitalia, hypogonadism (severe), delayed hair growth (moderate); decreased life expectancy (severe)	Brown et al. 2000; Li et al. 2009
Inhbc^−/−	No effects on development, liver cytoarchitecture, function, or regenerative capacity	Lau et al. 2000
Inhbe^−/−	No effects on development, liver cytoarchitecture, function, or regenerative capacity	Lau et al. 2000
Inha^−/−	Gonadal sex cord stromal and adrenal tumors, cachexia, absent parietal cells in the glandular stomach, and hepatocellular necrosis	Matzuk et al. 1992
Activin receptor mutants
Acvr2^−/−	25% die perinatally from cleft palate/Pierre Robin sequence; males have delayed fertility; females are infertile	Matzuk et al. 1995b
Acvr2b^−/−	Perinatal lethal in a subset; left–right asymmetry and anteroposterior axis defects	Oh and Li 1997
Acvr1b^−/− (Alk4)	Embryonic lethal; disrupted primitive streak	Gu et al. 1998
dnAcvr1b (driven by CaMKII-α)	Dominant negative ActRIB expression in developing forebrain makes hippocampal neurons more susceptible to excitotoxic injury; reduced glutamatergic neurotransmission and impaired long-term potentiation	Muller et al. 2006
Bambi^−/−	Regulation of mechanisms involved in acute and chronic pain sensitivity; no apparent developmental defects	Chen et al. 2007; Tramullas et al. 2010
Acvr1c^−/− (Alk7)	Progressive hyperinsulinemia, reduced insulin sensitivity, fatty liver, impaired glucose tolerance, pancreatic islet enlargement, reduced fat accumulation, and partial resistance to diet-induced obesity	Andersson et al. 2008; Bertolino et al. 2008
Fst^−/−	Neonatal lethality because of respiratory failure, hypoplasia of respiratory musculature, abnormal skin, and craniofacial malformations	Matzuk et al. 1995d
Fst^−/−	Aberrant (short, curled) whisker development leads to secondary defects in whisker-associated trigeminal sensory function	Jhaveri et al. 1998
Fst^−/−	Ectopic coelomic vessel formation in developing female gonads	Yao et al. 2004
Fstl3^−/−	Increased pancreatic islet number and size, with β-cell hyperplasia, diminished white fat, and beneficial effects on glucose metabolism	Mukherjee et al. 2007
Tgfbr3^−/−	Tgfbr3 (betaglycan) knockout causes lethal proliferative defects in heart and apoptosis in liver, occurring at E13.5	Stenvers et al. 2003
Double and triple mutants
Inhba^−/−; Inhbb^−/−	Combined features of the single mutations with no additional defects	Matzuk et al. 1995d
Inhba^BK/BK; Inhbb^−/−	Symmetrical growth deficiency (severe), eyelid closure defect, prominence of external genitalia, hypogonadism (severe), delayed hair growth (moderate), decreased life expectancy (severe), decreased adipose (severe)	Brown et al. 2003
Inhbb^−/−; Fst^−/−	Rescue of Inhbb-mediated ectopic coelomic vessel formation in developing female gonads	Yao et al. 2006
Inhbb^−/−; Wnt4^−/−	Rescue of Inhbb-mediated ectopic coelomic vessel formation in developing female gonads	Yao et al. 2006
Inhbc^−/−; Inhbe^−/−	No effects on development, liver cytoarchitecture, function, or regenerative capacity	Lau et al. 2000
Acvr2^+/−; Acvr2b^+/−	Abnormal development of stomach, spleen, and endocrine pancreas	Kim et al. 2000
Acvr2^−/−; Acvr2b^+/−	Embryos fail to form an elongated primitive streak, causing disruption of the mesoderm formation	Song et al. 1999
Acvr2^+/−; Acvr2b^−/−	Late gestational or early neonatal lethality; modest effect on rostral development	Song et al. 1999
Acvr2^−/−; Acvr2b^−/−	Arrested at the egg cylinder stage and do not form mesoderm	Song et al. 1999
Inha^−/−; Acvr2^−/−	Gonadal tumor development but rescue of Inha^−/−cachexia and hepatocellular necrosis	Coerver et al. 1996
Inha^−/−; Fsh^−/−	Increased survival and milder tumor/cachexia phenotypes relative to Inha^−/− mice	Kumar et al. 1999
Inha^−/−; Ar^−/−	Inhibin/androgen receptor double mutants have increased survival and milder tumor/cachexia phenotypes relative to Inha^−/−mice	Shou et al. 1997
Inha^−/−; Esr1^−/−; Esr2^−/−	Protection from early gonadal tumorigenesis in males only. Single estrogen receptor (Esr) knockouts are not sufficient to confer a protective effect	Burns et al. 2003a
Inha^−/−; Lhb^−/−	Increased survival and milder tumor/cachexia phenotypes relative to Inha^−/− mice	Nagaraja et al. 2008
Inha^−/−; Inhbc^TG-CMV	Mitigates gonadal tumor progression and prevents cachexia	Gold et al. 2013
Inha^−/−; hpg/hpg	Disrupted ovarian folliculogenesis with arrest at the primary antral stage; male and female hypogonadism and sterility; suppression of gonadal/adrenal tumors and cachexia; immature seminiferous tubule-like structures in testes and ovaries	Kumar et al. 1996
Inha^−/−; Gdf9^−/−	Follicles progress to the multilaminar stage with nonsteroidogenic theca layer	Wu et al. 2004; Myers et al. 2013

Genotypes	Site of inactivation	Phenotypes	References
Conditional knockouts
Amhr2-Cre; Inhba^flox/−	Ovarian granulosa cells	Disruption results in 35% reduction in female fertility	Pangas et al. 2007
Amhr2-Cre; Inhba ^flox/−	Fetal Leydig cells	Failure of fetal testis cord elongation and expansion, decreased Sertoli cell proliferation, smaller adult testes, regional testicular dysgenesis, and reduced sperm production	Archambeault and Yao 2010
Amhr2-Cre; Inhba ^flox/−; Inhbb^−/−	Ovarian granulosa cells	Female infertility; increased functional corpora lutea	Pangas et al. 2007
Krt14-Cre; Acvr1bflox/flox	Skin epithelium	Variable hairlessness as a result of defects in hair cycling and hair-follicle development	Qiu et al. 2011

Genes	Expression	Promoters	Phenotypes	References
*Gain-of-function*
Activins and inhibins
Inhba	Testis	Metallothionein	Testicular degeneration	Tanimoto et al. 1999
Inhba	Epidermis	Keratin 14	Small body size, small ears and short tail, severe epidermal thickening, loss of subcutaneous adipose	Munz et al. 1999b
Inhba	Epidermis	Keratin 14	Enhanced skin tumorigenesis and malignancy, differential effects on T-cell proliferation	Antsiferova et al. 2011
Inhba	Forebrain	αCaMKII	Reduced anxiety-related behavior	Ageta et al. 2008
Inhba	Forebrain	Tet-off inducible	Effects on long-term potentiation and maintenance of long-term memory	Ageta et al. 2010
Inhbc	Widespread	CMV promoter	Male infertility, large inflamed liver, prostatic hypertrophy with epithelial hyperplasia	Gold et al. 2009
Inhbc	Liver	Plasmid transfer	Inhibits regenerative DNA synthesis in mouse liver after volume overload injury	Chabicovsky et al. 2003
Inhbc	Liver	Adenovirus transfer	Accelerates liver regeneration after partial hepatectomy in rats	Wada et al. 2005
Inhbe	Widespread	CMV-β actin	Reduced pancreatic weight, adipose replacement of pancreatic acini with islets preserved	Hashimoto et al. 2006
Inhbe	Liver	Plasmid transfer	Inhibits regenerative DNA synthesis in mouse liver after volume overload injury	Chabicovsky et al. 2003
Inha	Widespread	Metallothionein	Female subfertility because of reduced FSH levels; ovarian cysts, abnormal steroidogenesis, reduced testicular size	Cho et al. 2001; McMullen et al. 2001
Inha	Several tissues including gonads	Metallothionein	FSH reduced, LH increased; females 52% reduction in litter size; reduced ovulation; 50% reduction in sperm count but normal fertility	Cho et al. 2001
Inha	Liver	Inducible	Reduced testis size and block in ovarian folliculogenesis at early antral stage; reduced FSH levels; rescue of the Inha^−/− phenotype	Pierson et al. 2000
Activin/inhibin receptors, binding, and regulatory proteins
Acvr1b	Epidermis	Keratin 14	Delayed wound re-epithelialization	Bamberger et al. 2005
Fst	Liver, testis	Metallothionein	Leydig cell hyperplasia, infertility in males and females, thin uteri, small testes and ovaries, disheveled fur	Guo et al. 1998
Fst288	Normal Fst expression pattern	Targeted insertion	Fst knockin allele is sufficient for survival but results in female subfertility and premature ovarian follicle depletion	Kimura et al. 2010
Fst288	Normal Fst expression pattern	Fst regulatory sequences	Fst288 expression does not rescue the neonatal lethality of Fst^−/− mice	Lin et al. 2008
Fst315	Normal Fst expression pattern	Fst regulatory sequences	Rescue of Fst^−/− phenotype; female infertility, cystic ovaries, aberrant corpora lutea, uterine hypoplasia/inflammation, and distal vascular abnormalities	Lin et al. 2008