Species: mouse
Mutation name: None
type: null mutation
fertility: infertile - ovarian defect
Comment: Differential contributions of connexin37 and connexin43 to oogenesis revealed in chimeric reaggregated mouse ovaries. Gittens JE 2005 et al. The gap junction proteins connexin37 and connexin43 are required for ovarian folliculogenesis in the mouse. To define their respective roles in oogenesis, chimeric ovaries containing either null mutant oocytes and wild-type granulosa cells or the reverse combination were grafted to the renal capsules of immunodeficient female mice. After three weeks, the oocytes were tested for meiotic competence and fertilizability in vitro. Ovaries composed of connexin43-deficient oocytes and wild-type granulosa cells produced antral follicles enclosing oocytes that could develop to at least the two-cell stage, demonstrating that oocytes need not express connexin43 to reach maturity. Conversely, both follicle development and oocyte maturation were impaired in ovaries containing either wild-type oocytes and connexin43-deficient granulosa cells or connexin37-deficient oocytes and wild-type granulosa cells. Thus absence of connexin43 from granulosa cells or connexin37 from oocytes is sufficient to compromise both oocyte and follicle development. Wild-type oocytes paired with connexin37-deficient granulosa cells generated antral follicles containing oocytes that developed to at least the two-cell stage. Therefore, connexin37 absence from granulosa cells need not impair fertility in mice. Dye transfer experiments revealed persistent oocyte-granulosa cell coupling in those follicles, indicating functional compensation by another connexin. The results indicate that mouse oocytes do not need to express connexin43 in order to develop into meiotically competent, fertilizable gametes, but must express connexin37 for communication with granulosa cells, a requirement for oogenesis. ///////////////////////// Targeted disruption of the gene encoding the gap junction protein connexin37 (Cx37; alpha 4) results in female infertility. Mutant follicles are not observed to develop beyond early antral stages, and there is a lack of both observable mature Graafian follicles and ovulation. The oocytes are unable to acquire meiotic competence. Following oocyte failure, the residual follicular cells do not undergo atresia but rather transdifferentiate into luteal cells, resulting in a mutant ovary populated with numerous, inappropriate corpora lutea (Goodenough et al, 1999;

Species: mouse
Mutation name: None
type: null mutation
fertility: infertile - ovarian defect
Comment: Female infertility in mice lacking connexin 37. Simon AM 1997 et al. The signals regulating ovarian follicle development and the mechanisms by which they are communicated are largely undefined. At birth, the ovary contains primordial follicles consisting of meiotically arrested oocytes surrounded by a single layer of supporting (granulosa) cells. Periodically, subsets of primordial follicles undergo further development during which the oocyte increases in size and the granulosa cells proliferate, stratify and develop a fluid-filled antrum. After ovulation, oocytes resume meiosis and granulosa cells retained in the follicle differentiate into steroidogenic cells, forming the corpus luteum. It has been proposed that intercellular signalling through gap junction channels may influence aspects of follicular development. Gap junctions are aggregations of intercellular channels composed of connexins, a family of at least 13 related proteins that directly connect adjacent cells allowing the diffusional movement of ions, metabolites, and other potential signalling molecules. Here we show that connexin 37 is present in gap junctions between oocyte and granulosa cells and that connexin 37-deficient mice lack mature (Graafian) follicles, fail to ovulate and develop numerous inappropriate corpora lutea. In addition, oocyte development arrests before meiotic competence is achieved. Thus, cell-cell signalling through intercellular channels critically regulates the highly coordinated set of cellular interactions required for successful oogenesis and ovulation. /////////////////////////

Species: mouse
Mutation name: None
type: null mutation
fertility: infertile - ovarian defect
Comment: Gap junctional intercellular communication in the mouse ovarian follicle. Goodenough DA 1999 et al. A targeted disruption of the gene encoding the gap junction protein connexin37 (Cx37; alpha 4) results in female infertility. Mutant follicles are not observed to develop beyond early antral stages, and there is a lack of both observable mature Graafian follicles and ovulation. The oocytes are unable to acquire meiotic competence. Following oocyte failure, the residual follicular cells do not undergo atresia but rather transdifferentiate into luteal cells, resulting in a mutant ovary populated with numerous, inappropriate corpora lutea. These results indicate that the Cx37-containing gap junctions formed between oocyte and follicular cells permit bidirectional signalling between the two cell types. These junctions are required for oocyte growth and development during preantral stages of the follicle, and for the inhibition of follicle cell luteinization. An additional role for these junctions may be to permit transfer of cytoplasmic signals required to hold oocytes in meiotic arrest. Since the mutant follicles never acquire meiotic competence, this latter role for gap junctional communication cannot be tested in this model. /////////////////////////

Species: human
Mutation name:
type: naturally occurring
fertility: subfertile
Comment: A common African variant of human connexin 37 is associated with Caucasian primary ovarian insufficiency and has a deleterious effect in vitro. Bachelot A et al. (2017) Folliculogenesis requires communication between granulosa cells and oocytes, mediated by connexin-based gap junctions. Connexin 37 (Cx37)-deficient female mice are infertile. The present study assessed Cx37 deficiency in patients with primary ovarian insufficiency (POI). A candidate gene study was performed in patients and controls from the National Genotyping Center (Evry, France) including 58 Caucasian patients with idiopathic isolated POI and 142 Caucasian controls. Direct genomic sequencing of the coding regions of the GJA4 gene (encoding Cx37) was performed with the aim to identify a deleterious variant associated with POI and absent in ethnically matched controls. A single Cx37 variant absent in the control population was identified, namely a c.946G>A heterozygous substitution leading to a p.Gly316Ser variant that was present in two POI patients. This variant was absent in all Caucasian controls from various databases, and has been observed exclusively in African populations. This variant was identified to have a dominant negative effect in HeLa cells in vitro to alter connexon function (by 67.2±7.17%), as determined by Gap-fluorescence recovery after photobleaching. The alteration principally resulted from a decrease of cell surface connexons due to altered trafficking (by 47.73±8.59%). In marked contrast to this observation, a p.Pro258Ser variant frequent in all ethnic populations in databases had no functional effect in vitro. In conclusion, the present study reported on a Cx37 variant in two Caucasian POI patients, which was absent in control Caucasian populations, and which had a deleterious effect in vitro. It is therefore suggested that in the genetic context of the Caucasian population, this variant may contribute to POI.//////////////////