Activins and Inhibins: Roles in Development, Physiology, and Disease

Namwanje, Maria; Brown, Chester

doi:10.1101/cshperspect.a021881

Cited by 215 publications

(194 citation statements)

References 471 publications

(486 reference statements)

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“…FSH is necessary for normal Sertoli cell function in the male and in granulosa cells of the female, as shown by Fshb −/− mice, which do not express the β subunit of FSH (Kumar et al 1997). The inhibins and closely related activins were discovered (and named) based on their ability to inhibit and activate, respectively, FSH secretion from the pituitary (Burns and Matzuk 2002; Bilezikjian et al 2004; Namwanje and Brown 2016). The importance of activin signaling for FSH synthesis was confirmed in Acvr2 −/− mice that lack expression of one of the activin type II receptors, ActRII (also known as ActRIIA).…”

Section: The Tgf-β Family In Male Reproductionmentioning

confidence: 99%

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The TGF-β Family in the Reproductive Tract

Monsivais

Matzuk

Pangas

2017

Cold Spring Harb Perspect Biol

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The transforming growth factor β (TGF-β) family has a profound impact on the reproductive function of various organisms. In this review, we discuss how highly conserved members of the TGF-β family influence the reproductive function across several species. We briefly discuss how TGF-β-related proteins balance germ-cell proliferation and differentiation as well as dauer entry and exit in Caenorhabditis elegans. In Drosophila melanogaster, TGF-β-related proteins maintain germ stem-cell identity and eggshell patterning. We then provide an in-depth analysis of landmark studies performed using transgenic mouse models and discuss how these data have uncovered basic developmental aspects of male and female reproductive development. In particular, we discuss the roles of the various TGF-β family ligands and receptors in primordial germ-cell development, sexual differentiation, and gonadal cell development. We also discuss how mutant mouse studies showed the contribution of TGF-β family signaling to embryonic and postnatal testis and ovarian development. We conclude the review by describing data obtained from human studies, which highlight the importance of the TGF-β family in normal female reproductive fnction during pregnancy and in various gynecologic pathologies.

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Section: The Tgf-β Family In Male Reproductionmentioning

confidence: 99%

“…Activins are homodimers or heterodimers of β subunits (β A :β A , activin A; β B :β B , activin B; β A :β B , activin AB) and inhibins are heterodimers (α:β A , inhibin A; α:β B , inhibin B) (Namwanje and Brown 2016). Targeted inactivation of each of the corresponding genes has distinct phenotypes.…”

Section: The Tgf-β Family In Male Reproductionmentioning

confidence: 99%

The TGF-β Family in the Reproductive Tract

Monsivais

Matzuk

Pangas

2017

Cold Spring Harb Perspect Biol

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“…That aside, the realization that the NSC effectively reduces the availability of all the partners involved in that complex (Activin A, ACVR1, and the type II receptors) and hence inhibits or reduces signaling by BMPs via the same receptors, propelled us to ask whether the NSC has biological roles. This question has, thus far, been largely unexplored as the majority of studies on Activin A have focused on its role as a signal-inducing ligand via ACVR1B (Makanji et al, 2014;Namwanje & Brown, 2016).…”

Section: Discussionmentioning

confidence: 99%

“…Activin A utilizes ACVR1B as its type I receptor in conjunction with the type II receptors ACVR2A, ACVR2B, and, to a lesser extent, BMPR2 to signal through Smad2/3 (Aykul et al, 2017). The biological functions of Activin A have been investigated widely using multiple approaches (Makanji et al, 2014;Namwanje & Brown, 2016) including reverse genetics experiments wherein the gene encoding for Activin A -Inhba -has been 'knocked out' (Archambeault & Yao, 2010;Matzuk et al, 1995;Pangas et al, 2007). The results of those experiments have been largely interpreted in the context of Activin A acting as an agonist of ACVR1B to induce Smad2/3 or other signaling pathways (Archambeault & Yao, 2010;Makanji et al, 2014;Namwanje & Brown, 2016;Pangas et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

The finger 2 tip loop of Activin A is required for the formation of its non-signaling complex with ACVR1 and type II Bone Morphogenetic Protein receptors

Aykul

et al. 2019

Preprint

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Activin A functions in BMP signaling in two ways: it either engages ACVR1B to activate Smad2/3 signaling or binds ACVR1 to form a non-signaling complex (NSC). Although the former property has been studied extensively, the roles of the NSC remain unexplored. The genetic disorder fibrodysplasia ossificans progressiva (FOP) provides a unique window into ACVR1/Activin A signaling because in that disease Activin can either signal through FOPmutant ACVR1 or form NSCs with wild type ACVR1. To explore the role of the NSC, we generated 'agonist-only' Activin A muteins that activate ACVR1B but cannot form the NSC with ACVR1. Using one of these muteins we demonstrate that failure to form the NSC in FOP results in more severe disease pathology. These results provide the first evidence for a biological role for the NSC in vivo and pave the way for further exploration of the NSC's physiological role in corresponding knock-in mice. Impact StatementThe signaling complex formed by Activin A and ACVR1 is operant in vivo and is required to temper the degree of heterotopic ossification in the genetic disorder fibrodysplasia ossificans progressiva.

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“…Finally, the testes secrete peptides of the inhibin/activin family, including α and βB subunits. The dimerization of an α and a βB subunit gives rise to inhibin B, whereas the dimerization of 2 β subunits gives rise to activins [reviewed by Namwanje and Brown, 2016]. Inhibin B is recognized as the major factor involved in the negative feedback of pituitary FSH secretion.…”

mentioning

confidence: 99%

Importance of Serum Testicular Protein Hormone Measurement in the Assessment of Disorders of Sex Development

Freire

Grinspon

Rey

2017

Sex Dev

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Commonly known for testosterone secretion, the testes also produce the protein hormones anti-müllerian hormone (AMH), inhibin B, and insulin-like factor 3 (INSL3). AMH and inhibin B are secreted by Sertoli cells, whereas INSL3 is a Leydig cell product. AMH is involved in fetal sex differentiation and induces the regression of the anlagen of the uterus and fallopian tubes. INSL3 participates in fetal testicular descent. Serum testicular protein hormone assessment can be very useful and complementary to testosterone measurements in patients with DSD. AMH and inhibin B determination is extremely helpful during childhood, when basal testosterone is normally low. Serum AMH and inhibin B above the female range are indicative of the presence of testicular tissue, and their circulating levels reflect the amount of functional Sertoli cells. In DSD patients with normal male levels of AMH and inhibin B, the diagnosis of gonadal dysgenesis can be ruled out, and isolated androgen secretion deficiency or androgen insensitivity should be suspected. In externally virilized XY patients with persistent müllerian ducts, serum AMH levels determine the diagnosis to AMH deficiency or resistance. At pubertal age, inhibin B levels serve to predict spermatogenic development.

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Activins and Inhibins: Roles in Development, Physiology, and Disease

Cited by 215 publications

References 471 publications

The TGF-β Family in the Reproductive Tract

The TGF-β Family in the Reproductive Tract

The finger 2 tip loop of Activin A is required for the formation of its non-signaling complex with ACVR1 and type II Bone Morphogenetic Protein receptors

Importance of Serum Testicular Protein Hormone Measurement in the Assessment of Disorders of Sex Development

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