Key Gene for Sperm, Egg Formation Identified at The Jackson Laboratory
| Date: December 2, 2003 |
Bar Harbor, Maine - Understanding of the intricate process of sperm and egg formation in mammals advanced significantly with a research report from scientists at The Jackson Laboratory.
The report, to be published in a forthcoming edition of Proceedings of the National Academy of Sciences (PNAS), details the identification of a new gene involved in a cell-division process called meiosis, which is essential for normal sperm and egg formation. This study is the first known instance of a meiosis gene being identified by forward-genetic approaches in mammals. Notably, this gene exists only in vertebrate organisms, but not lower species.
"Positional cloning and characterization of Mei1, a novel, vertebrate-specific gene required for normal meiotic chromosome synapsis in mice," is anticipated to publish in the PNAS Online Early Edition the week of 12/1/2003 to 12/5/2003.
Identification of genes that play a role in mammalian meiosis has been hindered because animals with mutations to those genes cannot reproduce. Consequently, scientists were limited to a reverse-genetics strategy of studying genes that are common to both mammals and lower-order organisms such as yeast, fruit flies, and worms. While many genes are common to both mammals and lower species, the reproduction process differs significantly from the higher to lower orders.
A team of Jackson Laboratory researchers headed by Senior Staff Scientist John C. Schimenti, Ph.D., studied mice descended from embryonic stem cells. The researchers identified Mei1, a gene that exists only in vertebrates and is expressed almost exclusively in gonads. The team further located Mei1 on chromosome 15 in mice. The gene controls formation of an unique protein, MEI1, which is necessary for normal chromosome alignment, one of the first steps in meiosis.
In the affected mice, the process of meiosis stops because of defects in the key steps of genetic recombination and alignment of maternal and paternal chromosomes. Normally, the meiotic chromosomes undergo a planned form of DNA damage called double strand breaks (DSB), which are then repaired by recombination.
Dr. Schimenti's team, which included Postdoctoral Associates Brian J. Libby and Laura G. Reinholdt, realized that the germ cells of Mei1 mutant mice did not utilize the recombination enzyme RAD51, normally associated with DSB repair and which associates with the breast cancer susceptibility genes BRCA1 and BRCA2. The scientists treated the mice with the anti-cancer drug cisplatin to induce DSB, and noted the cells began loading RAD51, indicating the repair mechanisms are functional. This led them to conclude the genetically programmed DSB induction in germ cells is defective in the mutant mice.
"We previously showed that cisplatin induces recombination in mice," Dr. Schimenti noted. "Another group used this to induce Rad51 utilization in mice with a similar defect in DSB induction.
"This advance is mainly in understanding the basic process of meiosis," he said, "which of course, is the key event in reproduction."
Contact(s): Jade Harmer, jade@jax.org, 207-288-6051
Joyce Peterson, joyce@jax.org, 207-288-6058
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