Publications by authors named "G W Kidder"

243 Publications

Retinoic acid enhances germ cell differentiation of mouse skin-derived stem cells.

J Ovarian Res 2018 Mar 1;11(1):19. Epub 2018 Mar 1.

Department of Physiology and Pharmacology, The University of Western Ontario and Children's Health Research Institute, 800 Commissioners Road East, London, ON, N6C 2V5, Canada.

Background: Retinoic acid (RA) signaling has been identified as a key driver in male and female gamete development. The presence of RA is a critical step in the initiation of meiosis and is required for the production of competent oocytes from primordial germ cells. Meiosis has been identified as a difficult biological process to recapitulate in vitro, when differentiating stem cells to germ cells. We have previously shown that primordial germ cell-like cells, and more advanced oocyte-like cells (OLCs), can be formed by differentiating mouse skin-derived stem cells. However, the OLCs remain unable to function due to what appears to be failure of meiotic initiation. The aim of this study was to determine the effect of RA treatment, during stem cell differentiation to germ cells, particularly on the initiation of meiosis.

Results: Using qPCR we found significant increases in the meiosis markers Stra8 and Sycp3 and a significant reduction in the meiosis inhibitor Nanos2, in the differentiating populations. Furthermore, OLCs from the RA treated group, expressed significantly more of the meiosis regulatory gene Marf1 and the oocyte marker Oct4. At the protein level RA treatment was found to increase the expression of the gap junction protein CX43 and the pluripotency marker OCT4. Moreover, the expression of SYCP3 was significantly upregulated and the localization pattern better matched that of control fetal ovarian cells. RA treatment also improved the structural integrity of the OLCs produced by initiating the expression of all three zona pellucida transcripts (Zp1-3) and improving ZP3 expression levels and localization. Finally, the addition of RA during differentiation led to an almost two-fold increase in the number of OLCs recovered and increased their in vitro growth.

Conclusion: RA is a key driver in the formation of functioning gametes and its addition during stem cell to germ cell differentiation improves OLCs entry into meiosis.
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http://dx.doi.org/10.1186/s13048-018-0390-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5831580PMC
March 2018

Roles of connexins in testis development and spermatogenesis.

Semin Cell Dev Biol 2016 Feb 11;50:22-30. Epub 2016 Jan 11.

INRS-Institut Armand-Frappier, University of Québec, 531 boul. des Prairies, Laval, Québec H7V 1B7, Canada.

The development and differentiation of cells involved in spermatogenesis requires highly regulated and coordinated interactions between cells. Intercellular communication, particularly via connexin43 (Cx43) gap junctions, plays a critical role in the development of germ cells during fetal development and during spermatogenesis in the adult. Loss of Cx43 in the fetus results in a decreased number of germ cells, while the loss of Cx43 in the adult Sertoli cells results in complete inhibition of spermatogenesis. Connexins 26, 32, 33, 36, 45, 46 and 50 have also been localized to specific compartments of the testis in various mammals. Loss of Cx46 is associated with an increase in germ cell apoptosis and loss of the integrity of the blood-testis barrier, while loss of other connexins appears to have more subtle effects within the seminiferous tubule. Outside the seminiferous tubule, the interstitial Leydig cells express connexins 36 and 45 along with Cx43; deletion of the latter connexin did not reveal it to be crucial for steroidogenesis or for the development and differentiation of Leydig cells. In contrast, loss of Cx43 from Sertoli cells results in Leydig cell hyperplasia, suggesting important cross-talk between Sertoli and Leydig cells. In the epididymis connexins 26, 30.3, Cx31.1, 32, and 43 have been identified and differentiation of the epithelium is associated with dramatic changes in their expression. Decreased expression of Cx43 results in decreased sperm motility, a function acquired by spermatozoa during epididymal transit. Clearly, intercellular gap junctional communication within the testis and epididymis represents a critical aspect of male reproductive function and fertility. The implications of this mode of intercellular communication for male fertility remains a poorly understood but important facet of male reproduction.
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http://dx.doi.org/10.1016/j.semcdb.2015.12.019DOI Listing
February 2016

Gap junction connexins in female reproductive organs: implications for women's reproductive health.

Hum Reprod Update 2015 May-Jun;21(3):340-52. Epub 2015 Feb 9.

Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, The University of Western Ontario and Children's Health Research Institute, London, Ontario N6C 2V5, Canada.

Background: Connexins comprise a family of ~20 proteins that form intercellular membrane channels (gap junction channels) providing a direct route for metabolites and signalling molecules to pass between cells. This review provides a critical analysis of the evidence for essential roles of individual connexins in female reproductive function, highlighting implications for women's reproductive health.

Methods: No systematic review has been carried out. Published literature from the past 35 years was surveyed for research related to connexin involvement in development and function of the female reproductive system. Because of the demonstrated utility of genetic manipulation for elucidating connexin functions in various organs, much of the cited information comes from research with genetically modified mice. In some cases, a distinction is drawn between connexin functions clearly related to the formation of gap junction channels and those possibly linked to non-channel roles.

Results And Conclusions: Based on work with mice, several connexins are known to be required for female reproductive functions. Loss of connexin43 (CX43) causes an oocyte deficiency, and follicles lacking or expressing less CX43 in granulosa cells exhibit reduced growth, impairing fertility. CX43 is also expressed in human cumulus cells and, in the context of IVF, has been correlated with pregnancy outcome, suggesting that this connexin may be a determinant of oocyte and embryo quality in women. Loss of CX37, which exclusively connects oocytes with granulosa cells in the mouse, caused oocytes to cease growing without acquiring meiotic competence. Blocking of CX26 channels in the uterine epithelium disrupted implantation whereas loss or reduction of CX43 expression in the uterine stroma impaired decidualization and vascularization in mouse and human. Several connexins are important in placentation and, in the human, CX43 is a key regulator of the fusogenic pathway from the cytotrophoblast to the syncytiotrophoblast, ensuring placental growth. CX40, which characterizes the extravillous trophoblast (EVT), supports proliferation of the proximal EVTs while preventing them from differentiating into the invasive pathway. Furthermore, women with recurrent early pregnancy loss as well as those with endometriosis exhibit reduced levels of CX43 in their decidua. The antimalaria drug mefloquine, which blocks gap junction function, is responsible for increased risk of early pregnancy loss and stillbirth, probably due to inhibition of intercellular communication in the decidua or between trophoblast layers followed by an impairment of placental growth. Gap junctions also play a critical role in regulating uterine blood flow, contributing to the adaptive response to pregnancy. Given that reproductive impairment can result from connexin mutations in mice, it is advised that women suffering from somatic disease symptoms associated with connexin gene mutations be additionally tested for impacts on reproductive function. Better knowledge of these essential connexin functions in human female reproductive organs is important for safeguarding women's reproductive health.
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http://dx.doi.org/10.1093/humupd/dmv007DOI Listing
November 2015

Connexin43 is required for the maintenance of multipotency in skin-derived stem cells.

Stem Cells Dev 2014 Jul 15;23(14):1636-46. Epub 2014 May 15.

1 Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, The University of Western Ontario , London, Ontario, Canada .

Expression of the gap junction protein, connexin43 (Cx43), begins early during embryogenesis and is maintained in many different cell types. Several stem cell populations have been shown to express Cx43 and to form functional gap junctions. While it is clear that Cx43 is critical to the function of many organs, whether the same is true for stem cells has not been clearly demonstrated. Recently, stem cells isolated from newborn mouse skin were shown to form oocyte-like cells (OLCs) in vitro, hence the present study focussed on the role Cx43 plays in the proliferation and differentiation of these cells. The stem cells express Cx43 and those from knockout mice (Cx43 KO) exhibited significantly reduced cell-cell coupling. Loss of Cx43 reduced the rate of cellular migration [Cx43 KO, 1.57±0.65 radial cell units (RCU); wildtype (WT), 5.57±0.37 RCU] but increased the proliferation rate of the stem cells (Cx43 KO, 29.40%±2.02%; WT, 12.76%±1.50%). The expression of the pluripotency markers OCT4 and Nanog were found to be reduced in the Cx43 KO population, suggesting an inhibition of differentiation potential. To test the differentiation ability, the stem cells were induced to form neuronal cell types in vitro. While both the WT and KO cells were able to form GFAP-positive astrocytic cells, only WT stem cells were able to form βIII tubulin-positive neurons. Similarly, the ability of the stem cells to form OLCs was ablated by the loss of Cx43. These data reveal a role for Cx43 in maintaining multipotency within the skin-derived stem cell population.
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http://dx.doi.org/10.1089/scd.2013.0459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4086243PMC
July 2014

Precision occlusal splints and the diagnosis of occlusal problems in myogenous orofacial pain patients.

Gen Dent 2014 Mar-Apr;62(2):24-31

Myogenous orofacial pain is a common nondental pain. There is an unresolved debate on the etiology of this problem. Research has shown that occlusal interferences affect masticatory muscle comfort, coordination, and function. Resolution of these problems with precise occlusal correction indicates that dental occlusion is a causative or contributory factor in myogenous orofacial pain. However, some studies fail to confirm this and instead conclude that occlusion is unrelated to masticatory muscle pain or dysfunction. An explanation for this discrepancy in findings is that these nonconfirmatory studies had not documented any pretreatment or corrected occlusion. Diagnostic casts mounted in centric relation and precision occlusal splints are accurate modalities to diagnose the occlusal problem and its correction in a patient with myogenous orofacial pain. Computerized digital occlusal analysis provides objective data of occlusal contact time and force to accurately assess diagnosis and treatment. The rationale and requirements for proper occlusal splint fabrication with a verified therapeutic occlusion are presented.
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April 2016
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