The alpha6 integrin subunit participates in the formation of both alpha6 beta1 and alpha6 beta4 laminin receptors, which have
been reported to play an important role in cell adhesion and migration and in morphogenesis.
NCBI Summary:
Integrins are heterodimeric proteins made up of alpha and beta subunits. At least 18 alpha and 8 beta subunits have been described in mammals. Integrin family members are membrane receptors involved in cell adhesion and recognition in a variety of processes including embryogenesis, hemostasis, tissue repair, immune response and metatastatic diffusion of tumor cells. The protein encoded by this gene is a beta subunit. Six alternatively spliced variants have been found for this gene which encode five proteins with alternate carboxy termini.
General function
Receptor, Cell adhesion molecule
Comment
He ZY, et al reported that None of the integrins known to be present on the mouse egg or to be ADAM receptors are essential for sperm-egg binding and fusion.
Antibody inhibition and alpha6beta1 ligand binding experiments indicate that the egg integrin alpha6beta1 functions as a receptor for sperm during gamete fusion; yet, eggs null for the alpha6 integrin exhibit normal fertilization. Alternative integrins may be involved in sperm-egg binding and fusion and could compensate for the absence of alpha6beta1. Various beta1 integrins and alphav integrins are present on mouse eggs. Some of these integrins are also reported to be receptors for ADAMs, which are expressed on sperm. Using alpha3 integrin null eggs, the authors found that the alpha3beta1 integrin was not essential for sperm-egg binding and fusion. Studeis using oocyte-specific, beta1 integrin conditional knockout mice found that the beta1 integrin null eggs were fully functional in fertilization both in vivo and in vitro. Furthermore, neither anti-mouse beta3 integrin function-blocking monoclonal antibody (mAb) nor alphav integrin function-blocking mAb inhibited sperm binding to or fusion with beta1 integrin null eggs. Thus, function of beta3 or alphav integrins does not seem to be involved in compensating for the absence of beta1 integrins. These results indicate that none of the integrins known to be present on mouse eggs or to be ADAM receptors are essential for sperm-egg binding/fusion, and thus, egg integrins may not play the role in gamete fusion previously attributed to them.
The physiological role(s) of integrins was
investigated by Fujiwara H et al using in vitro human granulosa cell culture and in vivo mouse ovulation model. In human luteinizing granulosa
cell culture obtained from the patients undergoing in vitro fertilization treatment, laminin, which is a ligand for integrin alpha
6 beta 1, suppressed the production of progesterone by granulosa cells. On the other hand, the anti-alpha 6 monoclonal
antibody (mAb) GoH3, which partially inhibits the interaction between integrin alpha 6 beta 1 and laminin, enhanced
production of progesterone by 2-fold of the control under the culture with laminin, indicating that integrin alpha 6 beta 1
regulates the luteinization of human granulosa cell during the periovulatory phase. In an immature superovulated 13-day-old
ICR (CD-1) mice model, intraperitoneal administration of GoH3 induced successful ovulation, showing that integrin alpha 6 beta 1 is related to gonadotropin-induced follicular
growth.
DNA fragmentation (apoptosis) was studied during the follicular, periovulatory and luteal phase in the marmoset monkey
ovary by means of terminal transferase mediated in situ nick end labeling, and correlated with immunohistochemical
localization of integrins (beta 1, alpha 2 and alpha 6 subunits). Giebel J reported staining intensities for integrins beta 1 and alpha 6 were strong in intact primordial/primary, secondary and tertiary follicles. Integrin expression of granulosa cells was weak in atretic tertiary
follicles but not in atretic primary or secondary follicles. Double labeling revealed that DNA fragmentation was solely found
in granulosa cells of tertiary follicles displaying faint or absent staining for both integrin subunits. During the periovulatory
and the luteal phase, granulosa cells of atretic tertiary follicles bordering on the basal membrane, which were referred to as
luteinizing cells, expressed the beta 1 subunit as well as the alpha 2-integrin subunit whereas granulosa cells neighboring to
the antrum were apoptotic and negative for integrin immunoreactivity.
Fujiwara H, et al. reported that laminin suppresses progesterone production by human luteinizing granulosa cells via interaction with integrin alpha 6 beta 1.
The sperm antigen fertilin alpha/beta and the integrin complex alpha6beta1 present on the oolemma are two of the most
promising candidates to mediate gamete interaction. During growth, the plasma membrane of both hamster and mouse
zona-free oocytes acquires the capacity to fuse with acrosome-reacted sperm when oocytes reach the size of 25-30 microm in
diameter, suggesting changes in the membrane molecular composition.
Genes whose expression is detected by cDNA array hybridization: cell surface antigens, cell adhesion, receptors Rozenn Dalbi?Tran and Pascal Mermilloda
Expression regulated by
LH
Comment
Changes in mouse granulosa cell gene expression during early luteinization. McRae RS et al. Changes in gene expression during granulosa cell luteinization have been measured using serial analysis of gene expression (SAGE). Immature normal mice were treated with pregnant mare serum gonadotropin (PMSG) or PMSG followed, 48 h later, by human chorionic gonadotropin (hCG). Granulosa cells were collected from preovulatory follicles after PMSG injection or PMSG/hCG injection and SAGE libraries generated from the isolated mRNA. The combined libraries contained 105,224 tags representing 40,248 unique transcripts. Overall, 715 transcripts showed a significant difference in abundance between the two libraries of which 216 were significantly down-regulated by hCG and 499 were significantly up-regulated. Among transcripts differentially regulated, there were clear and expected changes in genes involved in steroidogenesis as well as clusters of genes involved in modeling of the extracellular matrix, regulation of the cytoskeleton and intra and intercellular signaling. The SAGE libraries described here provide a base for functional investigation of the regulation of granulosa cell luteinization.
Integrins were localized immunohistochemically in marmoset ovaries (Callithrix jacchus) of defined cycle stages by Giebel J et al . With
monoclonal antibodies against beta 1, alpha 2, alpha 3, and alpha 6 integrin subunits, immunoreactivity was predominantly
found in ovaries of the follicular phase. In the luteal phase, non-luteal cells, e.g. fibroblasts or endothelial cells expressed
beta 1, alpha 2, or alpha 6 integrins. Immunostaining for the beta 1 subunit was strongest in granulosa cells of all growing
follicles. Weak immunoreactivity was found in granulosa cells of atretic follicles, theca and interstitial cells. With the alpha
2 antibody, binding was evident in granulosa cells of many, but not of all, primordial and primary follicles. Expression of
alpha 2 was also found in luteinized granulosa cells of tertiary follicles. In growing follicles, immunoreactivity of alpha 3
was restricted to granulosa cells of early secondary follicles. Within the epithelium, staining was almost exclusively found in
granulosa cells bordering on the basal granulosa cell layer. In advanced stages of atresia, granulosa cells of antral follicles
expressed the alpha 3 subunit. Integrin alpha 6 expression was evident in granulosa cells of all growing follicles but was
absent during advanced stages of degeneration.
Follicle stages
Primary, Antral, Preovulatory, Corpus luteum
Comment
Zuccotti M et al
found that both alpha6 and beta1 genes are
expressed in female germ cells during all the stages of development analyzed, from 10.5 to 18.5 d.p. c., during oocyte
growth, and in ovulated eggs.
Phenotypes
Mutations
1 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: infertile - ovarian defect Comment: Mouse primordial germ cells lacking beta1 integrins enter the germline but fail to migrate normally to the gonads.
Anderson R, et al .
Primordial germ cells are the founder cells of the gametes. They are set aside at the initial stages of gastrulation in mammals, become embedded in the hind-gut endoderm, then actively migrate to the sites of gonad formation. The molecular basis of this migration is poorly understood. Here we sought to determine if members of the integrin family of cell surface receptors are required for primordial germ cell migration, as integrins have been implicated in the migration of several other motile cell types. We have established a line of mice which express green fluorescent protein in germline cells that has enabled us to efficiently purify primordial germ cells at different stages by flow cytometry. We have catalogued the spectrum of integrin subunit expression by primordial germ cells during and after migration, using flow cytometry, immunocytochemistry and RT-PCR. Through analysis of integrin beta1(-/-)-->wild-type chimeras, we show that embryonic cells lacking beta1 integrins can enter the germline. However, integrin beta1(-/-) primordial germ cells do not colonize the gonad efficiently. Embryos with targeted deletion of integrin subunit alpha3, alpha6, or alphaV show no major defects in primordial germ cell migration. These results demonstrate a role for beta1-containing integrins in the development of the germline, although an equivalent role for * integrin subunit(s) has yet to be established.