Pannexins and Connexins: Their Relevance for Oocyte Developmental Competence

Abstract

The oocyte is the major determinant of embryo developmental competence in all mammalian species. Although fundamental advances have been generated in the field of reproductive medicine and assisted reproductive technologies in the past three decades, researchers and clinicians are still trying to elucidate molecular factors and pathways, which could be pivotal for the oocyte's developmental competence. The cell-to-cell and cell-to-matrix communications are crucial not only for oocytes but also for multicellular organisms in general. This latter mentioned communication is among others possibly due to the Connexin and Pannexin families of large-pore forming channels. Pannexins belong to a protein group of ATP-release channels, therefore of high importance for the oocyte due to its requirements of high energy supply. An increasing body of studies on Pannexins provided evidence that these channels not only play a role during physiological processes of an oocyte but also during pathological circumstances which could lead to the development of diseases or infertility. Connexins are proteins that form membrane channels and gap-junctions, and more precisely, these proteins enable the exchange of some ions and molecules, and therefore they do play a fundamental role in the communication between the oocyte and accompanying cells. Herein, the role of Pannexins and Connexins for the processes of oogenesis, folliculogenesis, oocyte maturation and fertilization will be discussed and, at the end of this review, Pannexin and Connexin related pathologies and their impact on the developmental competence of oocytes will be provided.

Keywords: connexin; developmental competence; fertilization; maturation; oocyte; oogenesis; pannexin.

Figure 1

(A) Connexin and pannexin share a similar structure, despite the absence of sequence homology. Connexin and pannexin form functional connexon and pannexon hemichannels, re-spectively. Connexins and pannexins are transmembrane proteins with four transmembrane do-mains, two extracellular loops, one cytoplasmic loop, and cytoplasmic N- and C-terminal domains. Connexin channels can assemble into a gap junction that mediates intercellular communication, while pannexin’s extracellular loop can have different degrees of glycosylation in mammalian cells, which prevent the formation of gap junctions, three variants of glycosylation are known: GLY0, GLY1, and GLY2. (B) The permeability properties of gap junction channels depend on their con-nexin composition: channels can be (1) homomeric-homotypic, (2) homomeric-heterotypic, or (3) heteromeric-heterotypic. Abbreviation: Glyc = glycosylation.

Figure 2

Scheme showing the regulation of gap-junctional communication (Cx43, Cx37) during the development of antral follicles prior to ovulation (A) and during meiotic resumption (B). (A) FSH hormone stimulates mRNA expression that codifies the Cx43/Cx37 synthesis of the gap-junctions, the amplification of functional channels, and consequently the integration to the metabolic activity. Mediated by the family mitogen-activated protein kinases, pre-ovulatory LH levels interrupt cell-cell communications by means of phosphorylation and modification of Cx43 protein conformation. This leads to interruption of the intercellular channels. The primary effect of the immediate response to LH is accompanied by elimination of the Cx43 protein, disappearance of gap-junction separation of the GCs from the oocyte. (B) LH stimulates the MAPK-dependent phosphorylation of Cx43, which induces the closure of Cx37and a decrease of cAMP inside the oocyte. In consequence, the maturation promoting factor (MPF) is activated and leads to resumption of meiosis and germinal vesicle (GV) breakdown. Abbreviations: Cx = Connexin, FSH = follicle stimulating Hormone, GJA = gene en-coding for connexins, LH = luteinizing hormone, ERK1/2 = extracellular signal-regulated kinases 1 and 2, MAPK = mitogen activated protein kinase, EGF = epidermal growth factor.

Figure 3

Mutation distribution of PANX1 and morphological appearance of oocytes retrieved from PANX1 channelopathy patients. (A) The gene Panx1 which encodes for PANX1 is located on chromosome 11 in humans. In four investigated families, four different mutations loci have been identified which led to a change in the amino acid sequence (highlighted in blue). (B) The upper part shows an exemplary degenerated oocyte in the germinal vesicle (GV) stage with shrunken ooplasm (dark grey), directly after oocyte retrieval; the lower part shows an exemplary degenerated zygote (fertilized oocyte) 30 h after Intra-Cytoplasmic-Sperm-Injection = ICSI, with the two pronuclei and extruded polar-bodies visible, but all specimens died at this stage. (C) Distribution of four disease-causing mutations in PANX1. All mutations were located in the cytoplasmic region and are highlighted as grey dots (according to [19]).