January 2006, Vol. 12, No. 1

Biomedicine
Council Researchers Wrestle with SUMO

Little is understood about the molecular mechanisms that regulate sperm production—knowledge that would be key to the development of male contraceptives. Recent research conducted in the laboratory of Patricia L. Morris, a cell biologist and pharmacologist at the Population Council’s Center for Biomedical Research, suggests that a protein known as SUMO-1 is involved in numerous aspects of this process. Gaining a greater understanding of SUMO’s role in producing sperm, or spermatogenesis, may lead to insights about male infertility and reveal potential targets for male contraception.

SUMOylation
SUMO—which comes in two varieties, SUMO-1 and SUMO-2/3—is a small protein that attaches to other proteins in a process known as SUMOylation. Cells use SUMOylation to alter proteins and influence their functions. SUMOylation can change a protein’s ability to remain in place, communicate with cells, and participate in the activation of genes. Although SUMO-1 is found in the testis, almost nothing was previously known about its reproductive role.

From rodent and human testes, Morris and her team isolated sperm, germ cells (which give rise to sperm), somatic cells (critical supporting testicular cells not giving rise to sperm), and intact seminiferous tubules (tiny tubes in the testes in which germ cells grow and mature and sperm are produced). The human material came from biopsies taken from men with normal spermatogenesis and men with defective spermatogenesis. These procedures were approved by an institutional review committee, and the men gave informed consent. All of the men were being treated for infertility at Weill Cornell Medical Center. The men with normal spermatogenesis were infertile as a result of blockage in the transport of sperm.

“In both humans and rodents, we followed the presence of SUMO-1 and sumoylated proteins during spermatogenesis, from the early proliferating germ cell to the mature sperm,” says Morris. “We have begun to characterize which proteins in which cells get sumoylated and at what point SUMOylation happens in the process of spermatogenesis.”

For the first time, this study provides compelling support that in both humans and rodents, the regulation of spermatogenesis may be mediated by interactions between SUMO-1 and a molecule known as the androgen receptor. The male sex hormone testosterone influences cells by binding to the androgen receptor. Interactions between androgens and their receptor are essential for spermatogenesis. SUMO-1 may alter the course of spermatogenesis by sumoylating the androgen receptor, thereby altering androgen-dependent processes. The researchers also found important differences in the activity of SUMO-1 in rodents and in people. During a stage in spermatogenesis called the pachytene stage, genes in the X and Y chromosomes (known as the sex chromosomes because they determine the sex of the offspring) become inactive. The genetic material then condenses into a structure known as the sex body. The findings suggest that SUMO-1 plays a different role in this process in people and in rodents.

SUMO-1 appears to be more abundant in the mouse sex body than in that of the human. In human pachytene spermatocytes, SUMO-1 and another factor that binds to DNA, known as a histone, show discrete patterns. In contrast, in rodent pachytene spermatocytes, the two proteins overlap the entire sex body.

Differences are also found in rodent and human SUMO-1 during meiosis—the type of cell division that results in sperm and eggs. Meiosis proceeds in several stages. During the first stage of meiosis in rodents, SUMO-1 is restricted to the sex chromosomes. In human spermatocytes during this stage, Morris’s data indicate that SUMO-1 likely plays a role in the organization of other chromosomal regions as well.

“For example, our data indicate that in human male germ cells but not in those of rodents, SUMO-1 may play a role in centromere/ kinetochore function,” says Morris. The centromere is the pinched “waist” of a chromosome. The kinetochore is the part of the centromere to which spindle fibers attach during cell division. The spindle fibers help to separate the chromosomes properly into the resulting daughter cells. In most organisms (other than bacteria and algae), the molecular mechanisms that ensure accurate chromosome segregation during cell division are critical to maintaining the normal number of chromosomes. If a mechanism, such as the one facilitated by the kinetochore, is disrupted, meiosis could result in sperm or eggs that have more or less than the normal number of chromosomes. Embryos that result from such sperm or eggs are likely to miscarry or develop into infants with significant birth defects, such as Down syndrome.

Comparing SUMOylation in humans and rodents may provide important insights into centromere formation and kinetochore assembly.

Source
Vigodner, Margarita, Tomomoto Ishikawa, Peter N. Schlegel, and Patricia L. Morris. Forthcoming. “SUMO-1, human male germ cell development and the androgen receptor in the testis of men with normal and abnormal spermatogenesis,” American Journal of Physiology: Endocrinology and Metabolism (Translational Series). (doi:10.1152/ajpendo.00527.2005) (offsite abstract)

Vigodner, Margarita and Patricia L. Morris. 2005. “Testicular expression of small ubiquitin-related modifier- 1 (SUMO-1) supports multiple roles in spermatogenesis: Silencing of sex chromosomes in spermatocytes, spermatid microtubule nucleation, and nuclear reshaping,” Developmental Biology 282: 480–492.

Outside funding
George Frederick Jewett Foundation, F. M. Kirby Foundation, and National Institutes of Health

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