The research has not yet been conducted using human tissue, but Haifan Lin, an associate professor of cell biology at Duke and senior author of the study, suspects that the human counterpart of miwi, called hiwi, is probably also associated with infertility in men. The study could eventually lead to genetic testing for the human form of the miwi gene, Lin said.
Piwi and miwi stem from the piwi family of genes known to be associated with the division of reproductive stem cells, which are the immature cells that can proliferate and mature to become adult sperm cells.
"This study presents the first definitive evidence that the piwi gene family has an essential function in the mammalian male reproductive system," said Lin, who is senior author of the paper in the June 7, 2002, issue of Developmental Cell.
In a related paper that appears in the June 6, 2002 issue of Oncogene, Lin describes the connection between the human homologue of piwi, called hiwi, and testicular cancer. (Please visit http://www.
There are a number of genes linked to male infertility, but only two, which includes miwi and crem, have been directly linked to sperm production as master regulators, Lin said.
When the miwi gene is defective or missing, it can lead to complete sterility in mice, he said.
"We show that this gene, miwi, instructs the making of a protein that binds to messenger RNAs to control their life span," Lin said. Messenger RNAs, which constitute the genetic instructions for proteins, are copied from DNA to be used to direct the cell's protein-making machinery.
"In turn, these messenger RNAs control the process of sperm production. In short, the protein MIWI, which is encoded by this gene is a master protein responsible for turning genes on and off during the process of sperm formation," he said.
The testes of mice with a defective miwi gene were, on average, 29 percent smaller by weight and did not produce any sperm.
The research, which was funded by the National Institutes of Health and the David and Lucile Packard Foundation of Los Altos, California, uses gene knockout technology in which Lin bred a mouse lacking the miwi gene, which was linked to chromosome 5.
The miwi gene is a member of the piwi gene family identified by Lin in 1997. The piwi genes were first isolated in Drosophila, or fruit flies, and have since been linked to reproductive stem cell function, ovarian tumors and infertility in fruit flies. Lin found that by removing the gene in fruit flies, the reproductive stem cells, called germline stem cells, would be depleted.
Now, the same family of genes has been linked to infertility in male mice. Lin is confident that the gene infertility link he found in mice, will one day apply to humans.
"In Developmental Cell, we show that without this gene, or if there is an underactive form of the gene, infertility in mice is the end result. We've also shown this in fruit flies and nematodes. Given the evolutionary closeness between mice and humans, it is very likely that a defective hiwi gene will affect humans in the same manner as well," Lin said.
According to the National Institute of Child Health and Human Development (NICHD), there are approximately 2.6 million infertile married couples in the U.S. Male infertility is a factor in approximately 40 percent of those cases.
The study was co-authored by Wei Deng, a postdoctoral fellow in the Lin laboratory.
For more information about male infertility, please visit the NICHD Web site at http://www.