The Secrets of Fertile Gamete

April 24-30, 2016 has been designated National Infertility Awareness Week by RESOLVE, the National Infertility Association.  Basic research plays an important role in our understanding of infertility.  Here, BPS member Polina Lishko, Department of Molecular and Cell Biology
University of California, Berkeley,  shares information about her research on male infertility, what makes human sperm fertile, and the path that brought her to use her biophysics background in the field of reproductive biology.  

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Infertility constitutes a global problem, with male infertility contributing to half of all cases. About 80% of male infertility cases are considered idiopathic, which means we don’t know the cause. The only available treatment in such cases is limited to assisted reproductive technologies. This huge gap in our understanding of etiology of male infertility is partially attributed to our insufficient knowledge of physiology of human sperm cells. Frankly, we still do not fully understand sophisticated machinery that regulates human sperm motility and their fertilizing potential. Sperm cells or spermatozoa as we call them, are diverse and species specific not only in their morphology or overall appearance, but also in their choice of molecular mechanisms that drive fertility. Essentially, what works for mouse or sea urchin sperm, may not necessarily work for human spermatozoa. This is why our lab and other reproductive biology laboratories embark on the comprehensive study to define what makes human sperm fertile. Our ultimate goal is either decrease sperm fertility by developing novel contraceptives or increase sperm fertilizing potential to help infertile couples to conceive. But the first step in this task- is to define what makes human sperm fertile and what impacts this ability. Once one knows all major regulatory units of human sperm cell, one can develop a comprehensive diagnostic test that could help men test their fertility potential. This knowledge also will be helpful to develop novel contraceptives for both men and women, and ultimately, this knowledge will be vital to help infertile couples.

My scientific journey into reproductive biology was not straightforward. I was trained as biophysicist and neuroscientist and has spent significant portion of the graduate and postdoctoral research studying how ion channels regulate excitability of neurons, as well as studying molecular mechanisms of vision and pain. However, ion channels are important regulatory switches in many different cell types, and they have long been suspected to play huge role in physiology of gametes. The area of sperm ion channel physiology was relatively terra incognita in comparison to neuroscience and muscle physiology, and I was very excited to go there and explore. Dr. Stanley Meizel, well-known reproductive biologist, once called sperm cell a neuron with a tail, and this is indeed quite smart comparison. While sperm cell are not known to generate action potential, they resemble sensory neurons in their ability to react to various physiological cues provided by female reproductive tract and use these cues to successfully navigate in their search for the egg.

So, in late 2007, while being a postdoctoral fellow at UCSF, I decided to begin my unforgettable and fun journey into reproductive biology. This path was not without a certain risks. While reproductive biology is very important and exciting field of research, paradoxically, it is one of the least funded one. For example, NICHD funding rate is way below 10%, and very few extramural funding opportunities currently exist for students and postdoctoral researchers who decide to devote their research to reproductive biology. Myself, I have been struggling for several years to secure NIH funding, and while my lab is currently fortunate for being supported by two NIH grants: NIGMS (R01) and NICHD (R21), as well as by private funding from Pew Charitable Trust (thanks to the neuroscience portion of my research) and Alfred P. Sloan Foundation, we need to secure more research support, as the work we do requires significant investments.

various mammalian sperm

Fig. 1. Examples of sperm morphological diversity. Spermatozoa of different species are shown with cytoplasmic droplets indicated by yellow arrows. Shown are: human (Hs; Homo sapiens), mouse (Mm; Mus musculus), rat (Rn; Rattus norvegicus), rhesus macaque (Mmu; Macaca mulatta), boar (Sd; sus scrofadomesticus), and bull (Bt; Bos taurus) sperm cells.

Why should we study reproductive biology and what is there for me, may you ask? Reproductive biology field holds many surprises for everyone, and has unlimited translational potential. For example, while working on identification of non-genomic progesterone receptor of human sperm, we have uncovered a novel signaling pathway that links steroid hormones with endogenous cannabinoids. And this bioactive lipid signaling is not sperm specific, but likely plays role in various tissues. Why is this important? Steroid hormones, such as progesterone, estrogen, testosterone or other steroids control fundamental organism function by regulating gene expression via their cognate nuclear receptors. However, fast and potent non-nuclear membrane signaling can also be initiated by steroids. Such phenomena as sperm activation, egg maturation and progesterone–induced analgesia are operated via a non-nuclear pathway, the key molecular regulators of which remained unknown. After five years of search for sperm membrane progesterone receptor we have finally revealed its molecular identity- monoacylglycerol lipase ABHD2. This protein is highly expressed in sperm, possesses progesterone-stimulated hydrolase activity and directly regulate sperm principal calcium channel that is crucial for male fertility. But what we actually found, is an unconventional pathway that links steroid hormones with the levels of bioactive lipids, such as endocannabinoid monoacylglycerol and arachidonic acid. ABHD2 is a member of large ABHD family of lipid enzymes, and it is possible that other members of the same family could be influenced by other steroids in similar manner. Of course, this hypothesis requires rigorous testing and we hope that it will be done in the near future. ABHD2 is not sperm specific: it is highly expressed in testis, microglia and lungs, and all these tissues are known to be regulated by endocannabinoid monoacylglycerol- the bioactive lipid that is eliminated by ABHD2 in progesterone-dependent manner.  Therefore, targeting ABHD2 in neurons or lungs may provide a new target for novel pharmacological approaches to improve pain management, as well as treat respiratory diseases. ABHD2 can also serve as a biomarker for male fertility and may help clinicians understand why some couples are unable to conceive naturally.

The link between steroids and endocannabinoids is just one of the many surprises that gametes hold in their treasure box. These cells are more sophisticated than what we think of them and will reward greatly those researchers who dare to wonder in the unexplored fields of reproductive biology.

–Polina Lishko

 

 

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