MHR : Basic Science of Reproductive Medicine - Volume 19, Issue 12, December 2013
Tribute to Robert Edwards

The December issue of MHR is a Celebration issue in tribute to Professor Sir Robert Edwards. It consists of an editorial and seven papers all freely available. Three invited reviews from eminent scientists summarise Bob Edward’s landmark findings in oocyte maturation, ovulation and sperm capacitation and describe the state-of-the-art today and the challenges for the future.

MHR : Basic Science of Reproductive Medicine -  Volume 19, Issue 11, November 2013

As summarized in their Editorial ‘MHR welcomes high quality basic reproductive research around pregnancy’ MHR Associate Editors Professor Jane Norman and Associate professor Stephen Tong welcome the fact that MHR’s interest does not stop at implantation, but straddles all of pregnancy.

Widespread DNA hypomethylation at gene enhancer regions in placentas associated with early-onset pre-eclampsia - Mol. Hum. Reprod. (2013) 19 (10): 697-708. doi: 10.1093/molehr/gat044 by J.D. Blair, R.K.C. Yuen, B.K. Lim, D.E. McFadden, P. von Dadelszen and W.P. Robinson

Early onset pre-eclampsia (EOPET) is a severe form of pre eclampsia which is a serious complication of pregnancy. With the ever increasing awareness of the importance of epigenetics Blair and colleagues studied DNA methylation in specific regions (gene enhancers) of the placentas associated with EOPET. Following on from their previous studies they increased the number of samples and importantly used a comprehensive microarray screening system interrogating 99% of know genes. They found that there were widespread methylation changes associated with EOPET which may be associated with placental function. Although further data is needed it raises the possibility of a non-invasive prenatal diagnosis of at-risk pregnancies – a very welcome development. 

Functional human sperm capacitation requires both bicarbonate-dependent PKA activation and down-regulation of Ser/Thr phosphatases by Src family kinases - Mol. Hum. Reprod. (2013) 19 (9): 570-580 doi:10.1093/molehr/gat033 by M.A. Battistone, V.G. Da Ros, A.M. Salicioni, F.A. Navarrete, D. Krapf, P.E. Visconti, and P.S. Cuasnicú

In order to fertilise the egg it is essential that the spermatozoon is capacitated. This was discovered in the early 1950’s yet we are still trying to determine the molecular details of this pivotal event. Battistone and colleagues have addressed a key part of the puzzle concentrating on how the cell initiates capacitation (within the first few minutes). In humans they investigated the activation of protein kinase A (PKA) (by bicarbonate) with specific emphasis on the modulating role of Ser/Thr phosphatases. Using a series of inhibitors they demonstrate that the initial activation of PKA substrates was dependent on an inhibition of the phosphatases by Src family kinases. This shows a very delicate control pattern which helps clarify the complex biochemical pathways involved in capacitation. This type of information deepens our understanding whilst at the same time offering potential avenues of manipulation for the putative non ART treatment of sperm dysfunction.

Mode of oocyte maturation affects EGF-like peptide function and oocyte competence - Mol. Hum. Reprod.  (2013) 19 (8): 500-509.  doi:10.1093/molehr/gat028 by D. Richani, L.J. Ritter, J.G. Thompson, and R.B. Gilchrist

The successful maturation of oocytes in vitro (IVM) is a major goal in ART that has yet to be reliably achieved. Richani and colleagues examined the role of the Epidermal Growth Factor (EGF) signalling pathway during mouse IVM. Supplementation of media with EGF like peptides (amphiregulin and epiregulin) significantly improved oocyte competence. Whilst there is a long way to go to obtain defined media producing a robust response in humans, this is a significant step along this tortuous pathway.

Genetic dissection of the pre-eclampsia susceptibility locus on chromosome 2q22 reveals shared novel risk factors for cardiovascular disease - Mol. Hum. Reprod. (2013) 19 (7): 423-437 doi:10.1093/molehr/gat011  by M.P. Johnson and co-workers

Pre-eclampsia is a serious and relatively common complication of pregnancy. An association between pre-eclampsia and later life cardiovascular disease (CVD) has been established providing a compelling reason to investigate the genetic risk factors involved in pre eclampsia. Johnson and colleagues performed a comprehensive and detailed assessment of susceptibility loci on chromosome 2q22. Novel SNP associations with pre-eclampsia and a number of CVD related traits are reported providing evidence for shared genetic mechanisms underlying pre eclampsia and CVD.

DPY19L2 gene mutations are a major cause of globozoospermia: identification of three novel point mutations - Mol. Hum. Reprod. (June 2013) 19(6): 395-404 doi:10.1093/molehr/gat018 by Fuxi Zhu, Fei Gong, Ge Lin, and Guangxiu Lu

Globozoospermia (round headed spermatozoa) is a rare heterogeneous condition. Men are sterile unless ICSI is used as a treatment option. In 2010 a homozygous deletion of a ~200kb region encompassing the DPY19L2 gene was identified as a significant cause. Following this there have been several confirmatory reports but as the condition is rare our knowledgebase on the condition and its causes is very limited. The paper by Zhu and colleagues examines 14 patients with complete globozoospermia, confirms that deletion of DPY19L2 is a cause in 4 cases and significantly identifies 5 patients with homozygous mutations (the remaining 5 had no identified mutation). These findings add a considerable amount of data – including novel mutations - on a rare condition, thus enhancing the possibility of relating genotypic variation with reproductive success and potentially providing a robust diagnostic marker.   

Molecular cloning and analysis of the Catsper1 gene promoter - Mol. Hum. Reprod. (May 2013) doi: 10.1093/molehr/gat003 by Minerva Mata-Rocha, Edith Alvarado-Cuevas, Javier Hernandez-Sanchez, Doris Cerecedo, Ricardo Felix, Adriana Hernandez-Reyes, Emiliano Tesoro-Cruz, and Norma Oviedo 

Sperm motility is critical for fertility yet the mechanisms underlying it are poorly understood. However technological developments in imaging and calcium signalling are revolutionising our understanding. A key channel involved in controlling calcium entry into the cell is CatSper. Sperm from mice null for CatSper show reduced progressive motility and fail to hyperactivate rendering them incapable of fertilization. CatSper genes are exclusively expressed in the testis during spermatogenesis. However their role in human infertility has yet to be delineated. Minerva Mata Roca and Norma Oviedo and team from Mexico have provided an important new insight into this problem. Using a variety of techniques including in vitro and in vivo transcription studies they have characterised the promoter region of CatSper 1 – in mice and humans. This will provide key information for future studies of the regulation of the Catsper channel in germ cells and a strong foundation for better understanding of the mechanisms of sperm motility and fertilization.

The search for biomarkers of human embryo developmental potential in IVF: a comprehensive proteomic approach Mol. Hum. Reprod. (2013) 19(4): 250-263 doi:10.1093/molehr/gas063 by Nyalwidhe J., Burc T., Bocca S., et al.

Concomitant with the development of single embryo transfer has been the absolute requirement to select the best embryo for transfer. Whilst there have been many attempts to do this, new technologies have yet to be robustly tested. Sergio Oehninger and colleagues present novel data on the non-invasive assessment of expressed proteins/peptides using proteomics. Using culture media from day 3 embryos up to 14 differentially regulated peptides were identified. Multiple algorithms enabled significant association with pregnancy and implantation failure. This data is potentially very useful. Whilst independent studies are now required, perhaps the power of this type of technology is eventually being realised.

Investigation of the mechanisms by which the molecular chaperone HSPA2 regulates the expression of sperm surface receptors involved in human sperm–oocyte recognition,  Mol. Hum. Reprod. (2013) 19(3): 120-135 doi:10.1093/molehr/gas064 by Kate A. Redgrove, Amanda L. Anderson, Eileen A. McLaughlin, Moira K. O'Bryan, R. John Aitken and Brett Nixon

Remarkably, despite decades of research, the molecular details of how a human sperm interacts with an egg remains somewhat of a mystery.  Now a paper published in Molecular Human Reproduction by  Redgrove  and colleagues from Australia provides a unique insight into this fundamental interaction.  The human sperm, during its expression of fertilising capacity (a feature termed capacitation) exposes a series of proteins that allow the exposure on the head of the sperm of a key complex including arylsulfatase A which may be important for sperm zona interaction. This work emphasis the dynamic nature of the sperm plasmamebrane and identifies potential functions of multimeric protein complexes in the spermatozoon.

Galectin-1 influences trophoblast immune evasion and emerges as a predictive factor for the outcome of pregnancy by Tirado-González I, Freitag N, Barrientos G, et al. Mol Hum Reprod 2013; 19: 43-53.

Remarkably, despite decades of research, the molecular details of how a human sperm interacts with an egg remains somewhat of a mystery. Now a paper published in Molecular Human Reproduction by Redgrove and colleagues from Australia provides a unique insight into this fundamental interaction. The human sperm, during its expression of fertilising capacity (a feature termed capacitation) exposes a series of proteins that allow the exposure on the head of the sperm of a key complex including arylsulfatase A which may be important for sperm zona interaction. This work emphasis the dynamic nature of the sperm plasmamebrane and identifies potential functions of multimeric protein complexes in the spermatozoon.