The Jackson Laboratory Reproductive Genomics Program
JAX® NOTES Issue 507, Fall 2007
The goal of The Jackson Laboratory Reproductive Genomics Program, an NIH-funded collaboration among Drs. John Eppig and Mary Ann Handel of The Jackson Laboratory and John Schimenti at Cornell University, is to produce, characterize, and map new mouse models of infertility and make them available to the wider scientific community. Since the program was initiated a little over 4 years ago (JAX® NOTES. 2004), it has produced over 35 new mouse models of infertility. The models are being used to characterize the genes involved in human reproduction and to develop novel, safe, reliable contraceptives and infertility therapies for both men and women.
Alleviating Infertility, Developing New Contraceptives
Reproduction is complex, and many genes that regulate it are likely unknown, limiting the development of safe, reliable contraceptives and therapies for infertility. Most contraceptives are based on hormonal manipulation, physical barriers, and surgery. Chemical analogs, protein repressors, and vaccines are being studied, and a few have been used with limited success, but they are not completely safe or reliable. Eighty percent of infertility cases have no known cause. In the U.S., infertility affects either partner equally in approximately 10% to 15% of married couples. In women, it is usually due to failure to ovulate, blocked fallopian tubes, or uterine abnormalities (see Womens Health Channel Web site). In men, infertility may be due to many factors, including sperm disorders (such as sperm count, motility, and shape), lifestyle (including occupational risks, medications, and drug use), and anatomical problems (see Fertility LifeLines™ Web site).
Because infertile mutants identified by the Reproductive Genomics Program are otherwise perfectly healthy, they may help identify genes that function strictly in reproduction. Such genes may have totally unexpected roles (such as sperm-oviduct interaction and sperm-to-egg guiding systems) that aren't manifested by in vitro experiments. Discovering these genes may be the key to developing the next generation of contraceptives and infertility therapies.
Producing and Identifying New Infertility Models
To produce new infertility models, the Reproductive Genomics Program treats C57BL/6J (B6, 000664) males with ethylnitrosurea (ENU), a chemical mutagen that induces random, genome-wide, single base pair mutations in the mouse genome. The mutations may either completely or partly eliminate a gene's function. Once mutagenized, the B6 males become part of a unique mating scheme with C3HeB/FeJ (C3Fe, 000658) females. The scheme allows investigators to detect any ENU-induced recessive infertility mutants and to use markers polymorphic between B6 and C3Fe mice to identify mutated genes.
Infertile mice are detected via two phenotyping screens. The first screen simply assesses, by mating, whether or not a mutagenized mouse can reproduce. The second screen consists of two "fertility clinics," one for females and one for males. In the female clinic, females found to be infertile are euthanized, and their hormone levels, reproductive tracts, ovaries, follicles, and oocytes are carefully analyzed for any abnormalities. Oocytes from each mouse are collected, and their maturation, fertilization, and embryonic development are characterized in vitro. In the male clinic, infertile males are euthanized, and their testes, seminal vesicles, and epididymides are weighed (weights of these organs are initial indicators of spermatogenesis and endocrine status). Sperm are collected, and their numbers, morphology, motility, acrosomal status, and fertilizing ability are assessed.
If several infertile mice with the same phenotype are produced in a family, they are deemed potential mutants, and, when the phenotype is confirmed to be heritable, a breeding line is established. The chromosomal region harboring the mutation is mapped, and the mutant is posted on the Reproductive Genomics Web site and made available to other biomedical researchers.
Mutant Phenotypes Produced so Far
To date, the Reproductive Genomics Program has produced over 35 new models of infertility, most of them models of male infertility. The mutations affect either spermatogenesis or sperm function during fertilization. Mutations in female models result in ovaries that develop poorly, have no oocytes, or have improperly maturing follicles, oocytes that die inside the follicles or can't complete meiosis, and embryos that die before reaching the blastocyst stage. Mutations so far identified and mapped by the Program represent approximately 10% of the total infertility mutations documented throughout the history of mouse research
Obtaining Reproductive Mutants
You can find information about reproductive mutants either at the Reproductive Genomics Web site or at the JAX® Mice Research Models site. Live colonies of new mutants are maintained for a limited time, during which you may receive breeder pairs for the cost of shipping only. Thereafter, many of the models are available from our cryopreserved repository as frozen sperm or embryos (again for the cost of shipping only), or as reconstituted mice (for the cost of shipping and reconstitution) through our Cryorecovery Service.
For more detailed information about the Reproductive Genomics Program, including its mutagenesis strategy, statistical analyses, staff, mailing list registration, and helpful links, visit the Reproductive Genomics Web site.
Selected References
(Authors in bold are Jackson Laboratory scientists.)
Bannister L, Pezza R, Donaldson J, de Rooij D, Schimenti K, Camerini-Otero D, Schimenti J. 2007. Male-specific sterility in mice carrying a dominant, recombination-defective allele of the RecA homolog Dmc1. PLoS Biol 5:e105.
Handel MA, Lessard C, Reinholdt L, Schimenti J, Eppig JJ. 2006. Mutagenesis as an unbiased approach to identify novel contraceptive targets. Mol Cell Endo 250:201-5.
JAX® NOTES. 2004. The Jackson Laboratory is finding new mouse models of infertility. JAX® NOTES 496:1-2.
Lessard C, Lothrop H, Schimenti JC, Handel MA. 2007. Mutagenesis-generated mouse models of human infertility with abnormal sperm. Hum Reprod 22:159-66.
Lessard C, Pendola JK, Hartford SA, Schimenti JC, Handel MA, Eppig JJ. 2004. New mouse genetic models for human contraceptive development. Cytogenet Genome Res 105:222-7.
