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Developmental Biology - Sperm Formation

SKP1 Enzyme Could be Target for Male Infertility

The protein, SKP1, drives a key transition step in male meiosis, the cell division process that results in sperm...

While some of our body's cells divide in a matter of hours, the meiosis process for making sperm, takes about 14 days from start to finish. Fully six of those days are spent in the stage known as the pachytene, when pairs of chromosomes from an individual's mother and father align and connect.
"This stage is really important, as the chromosome pair needs to be aligned for exchange of genetic material between the two.

If anything goes wrong at this stage, it can cause a defect in meiosis and problems in the resulting sperm, leading to infertility, pregnancy loss, or birth defects."

P. Jeremy Wang PhD, Biologist, Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania, USA.

In a new paper in Science Advances, Wang and colleagues have identified an enzyme that plays a crucial role in maintaining this chromosomal pairing during the pachytene stage of meiosis. Without this protein, named SKP1, meiosis cannot proceed to metaphase, the next major developmental stage involved in generating sperm cells.

The finding may help overcome hurdles that have stood in the way of treating certain forms of male infertility — in which a man makes no sperm — but, in whom sperm's precursor cells, spermatogonia, can be found.
"Reproductive technologies, like in vitro fertilization, have made a huge difference for infertile patients, but the male needs to have at least some sperm. If the male has no sperm, then the only option is to use donor sperm. But if you can find pre-meiotic germ cells, they could be induced to go through meiosis and make sperm. SKP1 could then become part of a solution ensuring meiosis continues."

P. Jeremy Wang PhD

Wang is hopeful his finding will aid basic research on sperm development, which his and many other labs pursue.

"Right now we use animals to do our research; we don't have a cell culture system to produce sperm," Wang explains. "Manipulating SKP1 and the pathway in which it acts could allow us to set up an in vitro system to produce sperm artificially, which would be a boon for our studies."

The publication represents nearly a decade of work, led by Wang's postdoctoral researcher Yongjuan Guan, with major contributions from former postdoc Mengcheng Luo.

The team began focusing on SKP1 after conducting a screening test to look for proteins found in an area where paired chromosomes come together during the pachytene stage of meiosis. From earlier studies, researchers knew SKP1 also plays a role in cell division in cells throughout the body, not just sperm and eggs. Without it, cells die.

That fact forced the Penn Vet team to get creative to understand the protein's function. Unable to simply eliminate it, they created a model system in mice in which they could turn off the protein only in the germ cells and only in adulthood.
"Using this inducible, germ-cell-specific model, we found that taking away SKP1 caused chromosomes to prematurely separate."

P. Jeremy Wang PhD

• Experiments in developing eggs showed researchers that SKP1 is also required for females to maintain viable eggs. Oocytes, the cells that develop through meiosis to form mature eggs, that lacked SKP1 developed misaligned chromosomes and many eventually were lost.

• While the normal alignment process in the pachytene stage takes six days in mice, in the cells that lost SKP1, paired chromosomes separated far earlier. Scientists had hypothesized the existence of a metaphase competence factor, or some protein required for a cell to enter metaphase. Wang believes that SKP1 is that 'factor'.

• While introducing a compound known as okadaic acid to sperm precursor cells can coax them into an early entrance to metaphase, cells lacking SKP1 did not progress to metaphase.

In future work, Wang and his colleagues want to dig deeper into the mechanism of action by which SKP1 works to ensure cells can progress to metaphase, with the idea of eventually manipulating it to find strategies for addressing infertility and innovative laboratory techniques.
"Now that we know SKP1 is required, we are looking for the proteins it interacts with upstream and downstream so we can study this pathway."

P. Jeremy Wang PhD

The meiotic prophase I to metaphase I (PI/MI) transition requires chromosome desynapsis and metaphase competence acquisition. However, control of these major meiotic events is poorly understood. Here, we identify an essential role for SKP1, a core subunit of the SKP1–Cullin–F-box (SCF) ubiquitin E3 ligase, in the PI/MI transition. SKP1 localizes to synapsed chromosome axes and evicts HORMAD proteins from these regions in meiotic spermatocytes. SKP1-deficient spermatocytes display premature desynapsis, precocious pachytene exit, loss of PLK1 and BUB1 at centromeres, but persistence of HORMAD, yH2AX, RPA2, and MLH1 in diplonema. Strikingly, SKP1-deficient spermatocytes show sharply reduced MPF activity and fail to enter MI despite treatment with okadaic acid. SKP1-deficient oocytes exhibit desynapsis, chromosome misalignment, and progressive postnatal loss. Therefore, SKP1 maintains synapsis in meiosis of both sexes. Furthermore, our results support a model where SKP1 functions as the long-sought intrinsic metaphase competence factor to orchestrate MI entry during male meiosis.

Wang, Guan, and Luo's coauthors on the paper were Penn Vet's N. Adrian Leu, Jun Ma, and Gordon Ruthel; Penn School of Arts and Sciences Biology Department's Lukás Chmátal and Michael Lampson; and Cornell University's Jordana C. Bloom and John C. Schmienti. Luo is now a faculty member at China's Wuhan University.

Support for the work came from the National Institute of General Medical Sciences (grants GM118052 and GM122475), National Key Research and Development Program of China (Grant 2018YFC1003400), National Natural Science Foundation of China (Grant 31771588), Thousand Youth Talents Plant, and National Institute of Child Health and Human Development (grants HD082568 and HD057854).

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Apr 1 2020   Fetal Timeline   Maternal Timeline   News 

Activity of Skp1 protein is crucial to sperm formation. In a dividing sperm precursor cell, chromosomes (PINK) normally align in the middle (left). But, in cells without Skp1 (right), chromosomes don't align and are chaotically distributed around the cell.
CREDIT Wang laboratory.

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