The Central Role of Cadherins in Gonad Development, Reproduction, and Fertility. Piprek RP et al. (2020) Cadherins are a group of membrane proteins responsible for cell adhesion. They are crucial for cell sorting and recognition during the morphogenesis, but they also play many other roles such as assuring tissue integrity and resistance to stretching, mechanotransduction, cell signaling, regulation of cell proliferation, apoptosis, survival, carcinogenesis, etc. Within the cadherin superfamily, E- and N-cadherin have been especially well studied. They are involved in many aspects of sexual development and reproduction, such as germline development and gametogenesis, gonad development and functioning, and fertilization. E-cadherin is expressed in the primordial germ cells (PGCs) and also participates in PGC migration to the developing gonads where they become enclosed by the N-cadherin-expressing somatic cells. The differential expression of cadherins is also responsible for the establishment of the testis or ovary structure. In the adult testes, N-cadherin is responsible for the integrity of the seminiferous epithelium, regulation of sperm production, and the establishment of the blood-testis barrier. Sex hormones regulate the expression and turnover of N-cadherin influencing the course of spermatogenesis. In the adult ovaries, E- and N-cadherin assure the integrity of ovarian follicles and the formation of corpora lutea. Cadherins are expressed in the mature gametes and facilitate the capacitation of sperm in the female reproductive tract and gamete contact during fertilization. The germ cells and accompanying somatic cells express a series of different cadherins; however, their role in gonads and reproduction is still unknown. In this review, we show what is known and unknown about the role of cadherins in the germline and gonad development, and we suggest topics for future research.//////////////////E-Cadherin is a specific calcium ion-dependent cell adhesion molecule. In mice it expresses its adhesive function during preimplantation stage of development and in epithelial cells where it is remarkably concentrated in the intermediate junctions. Epithelial cadherin (E-cadherin) is one member of a family of intracellular calcium (Ca(2+))-dependent adhesion molecules that mediates selective cell-cell adhesion in a variety of species.
NCBI Summary:
This gene encodes a classical cadherin of the cadherin superfamily. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature glycoprotein. This calcium-dependent cell-cell adhesion protein is comprised of five extracellular cadherin repeats, a transmembrane region and a highly conserved cytoplasmic tail. Mutations in this gene are correlated with gastric, breast, colorectal, thyroid and ovarian cancer. Loss of function of this gene is thought to contribute to cancer progression by increasing proliferation, invasion, and/or metastasis. The ectodomain of this protein mediates bacterial adhesion to mammalian cells and the cytoplasmic domain is required for internalization. This gene is present in a gene cluster with other members of the cadherin family on chromosome 16. [provided by RefSeq, Nov 2015]
JNK signaling regulates E-cadherin junctions in germline cysts and determines primordial follicle formation in mice. Niu W et al. (2016) Physiologically, the size of the primordial follicle pool determines the reproductive lifespan of female mammals, while its establishment largely depends on a proper process of germline cyst breakdown during the perinatal period. However, the mechanisms regulating this process are poorly understood. Here we demonstrate that c-Jun amino-terminal kinase (JNK) signaling is crucial for germline cyst breakdown and primordial follicle formation. JNK was specifically localized in oocytes and its activity was increased as germline cyst breakdown progressed. Importantly, the disruption of JNK signaling with its specific inhibitor (SP600125) or knock-down technology (Lenti-JNK-shRNAs) resulted in significantly suppressed cyst breakdown and primordial follicle formation in cultured mouse ovaries. Our results show that E-cadherin is intensely expressed in germline cysts, and that its decline is necessary for oocyte release from the cyst. However, the inhibition of JNK signaling leads to aberrantly enhanced localization of E-cadherin at oocyte-oocyte contact sites. Meanwhile, WNT4 expression is upregulated after SP600125 treatment. Additionally, similar to SP600125 treatment, WNT4 overexpression delays cyst breakdown; and is accompanied by abnormal E-cadherin expression patterns. In conclusion, our results suggest that JNK signaling, which is inversely correlated with WNT4, plays an important role in perinatal germline cyst breakdown and primordial follicle formation by regulating E-cadherin junctions between oocytes in mouse ovaries.//////////////////
E- and N-cadherin expression and distribution during luteinization in the rat ovary. Machell NH 2003 et al.
Cadherins, a family of Ca(2+)-dependent cell adhesion molecules, play an important role in ovarian tissue remodelling processes. The aim of this study was to examine the expression pattern of E- and N-cadherin in rat preovulatory follicles, luteinizing follicles and corpora lutea. Immature female rats were treated with equine chorionic gonadotrophin (eCG) to promote preovulatory follicle development. At 48 h after eCG treatment, the rats were injected with an ovulatory dose of hCG. Ovaries were analysed by western blot analysis and immunofluorescence for E- and N-cadherin expression at 48 h after eCG injection, and at 24 and 72 h after hCG injection. Ovaries of cyclic adult rats were examined to assess whether the changes in the expression pattern of cadherin were in agreement with those of the gonadotrophin-treated rats. Finally, expression of E-cadherin in luteinizing granulosa cells in vitro was assessed by RT-PCR and western blot analysis. Immunofluorescence results indicate that E-cadherin is expressed in the theca-interstial cells surrounding preovulatory follicles. N-cadherin expression is prominent in the membrana granulosa of these follicles. The initiation of luteinization with hCG leads to a decreased expression of N-cadherin in the membrana granulosa, whereas expression of E-cadherin starts within the luteinizing follicle. Both cadherins are prominently expressed in the fully formed corpus luteum at 72 h after hCG treatment. Immunofluorescence results revealed that the patterns of E- and N-cadherin expression in the gonadotrophin-treated rats were similar to those of the cyclic adult rats. Western blot analysis reflected similar changes for N-cadherin in the ovaries of both the cyclic adults and gonadotrophin-treated rats; however, they were different in E-cadherin expression. The expression of E-cadherin mRNA and protein was induced in vitro in luteinized granulosa cells. These results support the hypothesis that modulation of cadherin expression is an integral component of remodelling processes, including corpus luteum formation, in the ovary. The results also indicate that expression of E- and N-cadherin in granulosa-lutein cells appear to be under hormonal control.
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Expression of E-Cadherin and N-Cadherin in Perinatal Hamster Ovary: Possible Involvement in Primordial Follicle Formation and Regulation by Follicle-Stimulating Hormone. Wang C et al. We examined the expression and hormonal regulation of E-cadherin (CDH1) and N-cadherin (CDH2) with respect to primordial follicle formation. Hamster Cdh1 and Cdh2 cDNA and amino acid sequences were more than 90% similar to those of the mouse, rat, and human. Although CDH1 expression remained exclusively in the oocytes during neonatal ovary development, CDH2 expression shifted from the oocytes to granulosa cells of primordial follicles on postnatal day (P)8. Subsequently, strong CDH2 expression was restricted to granulosa cells of growing follicles. Cdh2 mRNA levels in the ovary decreased from embryonic d 13 through P10 with a transient increase on P7, which was the day before the appearance of primordial follicles. Cdh1 mRNA levels decreased from embryonic d 13 through P3 and then showed a transient increase on P8, coinciding with the formation of primordial follicles. CDH1 and CDH2 expression were consistent with that of mRNA. Neutralization of FSH in utero impaired primordial follicle formation with an associated decrease in Cdh2 mRNA and CDH2, but an increase in Cdh1 mRNA and CDH1 expression. The altered expression was reversed by equine chorionic gonadotropin treatment on P1. Whereas a CDH2 antibody significantly reduced the formation of primordial and primary follicles in vitro, a CDH1 antibody had the opposite effect. This is the first evidence to suggest that primordial follicle formation requires a differential spatiotemporal expression and action of CDH1 and CDH2. Further, FSH regulation of primordial follicle formation may involve the action of CDH1 and CDH2.
CDC14B Acts Through FZR1 (CDH1) to Prevent Meiotic Maturation of Mouse Oocytes. Schindler K et al. Meiotic maturation in oocytes is a prolonged process that is unique because of cell cycle arrests at prophase of meiosis I (MI) and at metaphase of meiosis II (MII). Fluctuations in cyclin-dependent kinase 1 (CDK1/CDC2A) activity govern meiotic progression, yet little is known about how these fluctuations are achieved. CDC14 is a highly conserved, dual-specificity phosphatase that counteracts the function of proteins phosphorylated by CDK. Mammals contain two CDC14 homologs, CDC14A and CDC14B. We report that CDC14B localizes with the meiotic spindle in mouse oocytes and, unlike somatic cells, it does not localize in the nucleolus. Oocytes that over-express CDC14B are significantly delayed in resuming meiosis and fail to progress to MII, whereas oocytes depleted for CDC14B spontaneously resume meiosis under conditions that normally inhibit meiotic resumption. Depletion of FZR1 (CDH1), a regulatory subunit of the anaphase-promoting complex/cyclosome (APC/C) that targets cyclin B1 (CCNB1) for ubiquitin-mediated proteolysis, partially restores normal timing of meiotic resumption in oocytes with excess CDC14B. These studies also reveal that experimentally altering CDC14B levels generates eggs with abnormal spindles and chromosome alignment perturbations. Our data indicate that CDC14B is a negative regulator of meiotic resumption and may regulate MI in mouse oocytes.
Expression of cadherin molecules was
demonstrated by Rufas et al in human oocyte using an anti-pan-cadherin antibody and
specific antibodies against the three classical cadherins: E- (epithelial),
P- (placental) and N- (neural) cadherins. Samples of
48 h old unfertilized oocytes were lysed and separated by
electrophoresis. Localization of cadherins was determined on intact, fixed,
permeabilized oocytes by
immunocytochemisty assessed by confocal microscopy. Immunoblotting with the
pan-cadherin antibody revealed a single
band of ~120 kDa in oocyte extracts. Oocytes presented all three classical cadherins with the appropriate molecular weights of 120?130
kDa. Following immunocytochemistry of human oocytes all cadherin
molecules were allocated predominantly to the
plasma membrane with only traces in the cytoplasm. It was concluded that cadherin
molecules are present on plasma membranes of both human spermatozoa and
oocytes and may play a role in the intricate
recognition process preceding gamete fusion.
APCcdh1 activity in mouse oocytes prevents entry into the first meiotic division. Reis A et al. Fully grown mammalian oocytes maintain a prophase I germinal-vesicle stage arrest in the ovary for extended periods before a luteinizing hormone surge induces entry into the first meiotic division. Cdh1 is an activator of the anaphase-promoting complex (APC) and APCcdh1 is normally restricted to late M to early G1 phases of the cell cycle. Here, we find that APCcdh1 is active in mouse oocytes and is necessary to maintain prophase arrest.
Prophase I arrest and progression to metaphase I in mouse oocytes are controlled by Emi1-dependent regulation of APCCdh1. Marangos P et al. Mammalian oocytes are arrested in prophase of the first meiotic division. Progression into the first meiotic division is driven by an increase in the activity of maturation-promoting factor (MPF). In mouse oocytes, we find that early mitotic inhibitor 1 (Emi1), an inhibitor of the anaphase-promoting complex (APC) that is responsible for cyclin B destruction and inactivation of MPF, is present at prophase I and undergoes Skp1-Cul1-F-box/betaTrCP-mediated destruction immediately after germinal vesicle breakdown (GVBD). Exogenous Emi1 or the inhibition of Emi1 destruction in prophase-arrested oocytes leads to a stabilization of cyclin B1-GFP that is sufficient to trigger GVBD. In contrast, the depletion of Emi1 using morpholino oligonucleotides increases cyclin B1-GFP destruction, resulting in an attenuation of MPF activation and a delay of entry into the first meiotic division. Finally, we show that Emi1-dependent effects on meiosis I require the presence of Cdh1. These observations reveal a novel mechanism for the control of entry into the first meiotic division: an Emi1-dependent inhibition of APC(Cdh1).
Expression regulated by
Comment
Ovarian localization
Oocyte, Granulosa, Theca, Luteal cells
Comment
Spatial regulation of APCCdh1-induced cyclin B1 degradation maintains G2 arrest in mouse oocytes. Holt JE et al. Within the mammalian ovary, oocytes remain arrested at G2 for several years. Then a peri-ovulatory hormonal cue triggers meiotic resumption by releasing an inhibitory phosphorylation on the kinase Cdk1. G2 arrest, however, also requires control in the concentrations of the Cdk1-binding partner cyclin B1, a process achieved by anaphase-promoting complex (APC(Cdh1) activity, which ubiquitylates and so targets cyclin B1 for degradation. Thus, APC(Cdh1) activity prevents precocious meiotic entry by promoting cyclin B1 degradation. However, it remains unresolved how cyclin B1 levels are suppressed sufficiently to maintain arrest but not so low that they make oocytes hormonally insensitive. Here, we examined spatial control of this process by determining the intracellular location of the proteins involved and using nuclear-targeted cyclin B1. We found that raising nuclear cyclin B1 concentrations, an event normally observed in the minutes before nuclear envelope breakdown, was a very effective method of inducing the G2/M transition. Oocytes expressed only the alpha-isoform of Cdh1, which was predominantly nuclear, as were Cdc27 and Psmd11, core components of the APC and the 26S proteasome, respectively. Furthermore, APC(Cdh1) activity appeared higher in the nucleus, as nuclear-targeted cyclin B1 was degraded at twice the rate of wild-type cyclin B1. We propose a simple spatial model of G2 arrest in which nuclear APC(Cdh1)-proteasomal activity guards against any cyclin B1 accumulation mediated by nuclear import.
Ryan et al. (1996) showed the presence of a 120-kDa protein, corresponding to E-cadherin, which was highest in fetal and neonatal ovaries and declined markedly (3- to 8-fold, p < 0.05) with maturity (16 wk to adult). In the adult ovary, E-cadherin was highest in ovarian surface epithelium (OSE) whereas in healthy follicles, granulosa cells had the highest levels. A significant decline (p < 0.05) in E-cadherin expression was evident in granulosa and theca cells from atretic follicles when compared with E-cadherin expression in cells of healthy follicles.
Maternal {beta}-catenin and E-cadherin in mouse development De Vries WN, et al 2004 .
The oocyte to embryo transition in metazoans depends on maternal proteins and transcripts to ensure the successful initiation of development, and the correct and timely activation of the embryonic genome. We conditionally eliminated the maternal gene encoding the cell adhesion molecule E-cadherin and partially eliminated the beta-catenin gene from the mouse oocyte. Oocytes lacking E-cadherin, or expressing a truncated allele of beta-catenin without the N-terminal part of the protein, give rise to embryos whose blastomeres do not adhere. Blastomere adhesion is restored after translation of protein from the wild-type paternal alleles: at the morula stage in embryos lacking maternal E-cadherin, and at the late four-cell stage in embryos expressing truncated beta-catenin. This suggests that adhesion per se is not essential in the early cleavage stage embryos, that embryos develop normally if compaction does not occur until the morula stage, and that the zona pellucida suffices to maintain blastomere proximity. Although maternal E-cadherin is not essential for the completion of the oocyte-to-embryo transition, absence of wild-type beta-catenin in oocytes does statistically compromise developmental success rates. This developmental deficit is alleviated by the simultaneous absence of maternal E-cadherin, suggesting that E-cadherin regulates nuclear beta-catenin availability during embryonic genome activation.
Follicle stages
Preovulatory, Corpus luteum
Comment
Khan-Dawood et al. (1997) have recently shown the presence of E-cadherin and of alpha- and gamma-catenins in human and baboon corpora lutea.
Khan-Dawood FS et al 1996 reported immunocytochemical localization and expression of E-cadherin,
beta-catenin, and plakoglobin in the baboon (Papio anubis)
corpus luteum.
E-cadherin was localized to the
peripheral cell membranes of luteal cells at all stages examined, except atretic corpora lutea, with the
strongest immunoreactivity in the early luteal phase. Both beta-catenin and plakoglobin were localized in
the cytoplasm of the luteal cells. Immunoreactivity for all three peptides was not observed in nonluteal
tissue. By Western analysis, abundant expression of E-cadherin was observed in the early luteal phase,
and the level of expression was significantly different from that observed in the mid- and late luteal
phase corpora lutea. In contrast, the levels of beta-catenin and plakoglobin were higher in the midluteal
phase compared to the early luteal phase.
Phenotypes
Mutations
2 mutations
Species: human
Mutation name: None
type: None fertility: None Comment:Risinger et al. (1994) identified a CTG-to-GTG transversion resulting in a leu711-to-val amino acid substitution in E-cadherin in an ovarian carcinoma. The wildtype allele was not lost.
Species: mouse
Mutation name: type: null mutation fertility: infertile - ovarian defect Comment: Tissue-specific knockout of E-cadherin (Cdh1) in developing mouse gonads causes germ cells loss. Piprek RP et al. (2019) The normal course of gonad development is critical for the sexual development and reproductive capacity of the individual. During development, an incipient bipotential gonad which consists of unorganized aggregate of cells, must differentiate into highly structured testis or ovary. Cell adhesion molecules (CAMs) are a group of proteins crucial for segregation and aggregation of different cell types to form different tissues. E-cadherin (Cdh1) is one of the CAMs expressed in the developing gonads. We used tissue-specific knockout of Cdh1 gene in Oct4+ germ cells and, separately, in Sf1+ somatic cells of developing gonads. The knockout of E-cadherin in somatic cells caused decrease in the number of germ cells, while the knockout in the germ cells caused their almost complete loss. Thus, the presence of E-cadherin in both the germ and somatic cells is necessary for the survival of germ cells. Although the lack of E-cadherin did not impair cell proliferation it enhanced apoptosis, which was a possible cause of germ cell loss. However, the somatic cells of the gonad differentiated normally into Sertoli cells in the testis cords, and into follicular cells in the ovaries. The testis and ovigerous cords maintained their integrity; they were covered by continuous basement membranes. The testicular interstitium with steroidogenic fetal Leydig cells did not show any noticeable changes. However, in the female gonads, because of the lack of germ cells, the ovarian follicles were absent. The sex determination and sexual differentiation of the gonad were not impaired. These results underscore an important role of E-cadherin in germ cell survival and gonad development.//////////////////