Although activins were discovered by virtue of their capacity to stimulate the production of
follicle-stimulating hormone by the pituitary gland and inhibins were initially characterized as FSH
inhibitors, activins and inhibins are dimeric proteins that share a common subunit. There are 3 activins (A, B, and A-B),
comprising different combinations of 2 closely related beta subunits (beta-A/beta-A; beta-B/beta-B; and beta-A/beta-B,
respectively) and 2 inhibins (A and B), consisting of 1 beta-subunit and an inhibin-specific alpha subunit (alpha/beta-A
and alpha/beta-B). Activins impinge on a much broader spectrum of cells than do inhibins; however, in those systems in
which both proteins are functional, they have opposing biologic effects. Activins are members of a family of
polypeptide growth factors that includes also the transforming growth factors-beta,
mullerian duct-inhibiting substance, and several bone morphogenetic proteins.
Mathews and Vale (1991) cloned an activin receptor cDNA by use of a method that has been used to clone other
receptors, such as that for erythropoietin. The cloning was based on the ability of the receptor to bind a labeled ligand
following expression of a cDNA library in mammalian cells. The cDNA coded for a protein of 494 amino acids
comprising a ligand-binding extracellular domain, a single membrane-spanning domain, and an intracellular kinase
domain with predicted serine/threonine specificity. On the basis of affinity-crosslinking studies, They identified 2 types of activin receptors. The type I receptor has a molecular size of 65 kD, while the molecular
size of the type II receptor is 85 kD.
General function
Receptor
Comment
Cellular localization
Plasma membrane
Comment
Ovarian function
Follicle endowment, Follicle development, Antral follicle growth, Germ cell development
Comment
Eramaa M, et al 1995 reported the expression of activin receptor mRNAs in cultured human granulosa-luteal cells.
Northern blot analysis indicated that cultured human GL cells as well as
freshly isolated preovulatory granulosa cells express the specific mRNAs for all
currently known serine/threonine kinase activin receptors, i.e. activin receptors I,
IB, II, and IIB.
Richards AJ, et al 1999 reported that activin and TGFbeta limit murine primordial germ cell
proliferation.
Mammalian primordial germ cells (PGCs) proliferate as they migrate from their
initial location in the extraembryonic mesoderm to the genital ridge, the gonadal
anlage. Once in the genital ridge, PGCs cease dividing and differentiate according
to their gender. Growth factor receptors encoded in RNA obtained from purified germ
cells were analyzed shortly after their arrival in the genital ridge. Receptors for two members of
the TGFbeta superfamily were found, TGFbeta1 and activin. As the signal-transducing domains of both receptor systems are highly conserved, the effects of both TGFbeta1 and activin on PGCs would be expected to be similar.
It was found that both ligands limited the accumulation of germ cells in primary PGC
cultures. BrdU incorporation assays demonstrated that either ligand inhibits PGC
proliferation. These results suggest that these signal transduction pathways are
important elements of the mechanism that determines germ cell endowment.
Otkay et al 2000 reported the interaction of Extracellular Matrix and Activin-A in the Initiation of Follicle
Growth in the Mouse Ovary.
Ovaries were collected
from 5-day-old mice and cultured for 10 days on polylysine, collagen, or
laminin in the presence or absence of recombinant
human activin-A. Follicle density, indices of follicle growth initiation
(primary:primordial follicle [PY:PD] and
primary:total follicle [PY:TF] ratios), ratios of multilayer follicle:total
follicle (ML:TF), and follicle growth rates were
compared between groups. Activin-A stimulated multilayer follicle
development in the presence of laminin (ML:TF
ratio), whereas it suppressed follicle growth
in collagen. Activin-A did not affect the
ML:TF ratio in the polylysine-treated groups. These results
suggest that extracellular matrix components and
activin-A interact with each other, and that they regulate follicle growth
initiation and multilayer follicle development.
Expression regulated by
Comment
Ovarian localization
Primordial Germ Cell, Granulosa, Luteal cells
Comment
da Silva SJ, et al reported the expression of activin subunits and receptors in the developing human ovary: activin A promotes germ cell survival and proliferation before primordial follicle formation.
The formation of the essential functional unit of the ovary, the primordial follicle, occurs during fetal life in humans. Factors regulating oogonial proliferation and interaction with somatic cells before primordial follicle formation are largely unknown. We have investigated the expression, localisation and functional effects of activin and its receptors in the human fetal ovary at 14-21 weeks gestation. Expression of mRNA for the activin betaA and betaB subunits and the activin receptors ActRIIA and ActRIIB was demonstrated by RT-PCR. Expression of betaA mRNA increased 2-fold across the gestational range examined. Activin subunits and receptors were localised by immunohistochemistry. The betaA subunit was expressed by oogonia, and the betaB subunit and activin receptors were expressed by both oogonia and somatic cells. betaA expression was increased in larger oogonia at later gestations, but was low in oocytes within newly formed primordial follicles. Treatment of ovary fragments with activin A in vitro increased both the number of oogonia present and oogonial proliferation, as detected by bromodeoxyuridine (BrdU) incorporation. These data indicate that activin may be involved in the autocrine and paracrine regulation of germ cell proliferation in the human ovary during the crucial period of development leading up to primordial follicle formation.