|
Oncogenesis, reproduction, and development in mice
Reproductive and embryonic development are complex processes which require the coordinated interaction of
multiple proteins. The overall research goals of my laboratory are directed at elucidating the critical proteins involved in
both normal and abnormal reproductive development. These studies are focusing on both extragonadal regulators such as
luteinizing hormone and follicle stimulating hormone and intragonadal regulators such as the inhibins, activins, and
growth/differentiation factor 9 (GDF-9). These latter proteins are members of the large TGF-β superfamily of secreted
growth factors and appear to play important roles in multiple tissues as endocrine, paracrine, and autocrine mediators during
both embryonic and adult development.
To characterize the roles of these proteins in mammalian reproduction and development, we have taken a systematic
approach to generate standard transgenic mice as well as "knock-out" mice deficient in a number of these genes using gene
targeting and embryonic stem (ES) cell technology. Analysis of the mice generated in these "gain of function" and
"loss of function" experiments have revealed the critical roles of several of these proteins in mammalian
reproduction, development, and oncogenesis. Initial studies to generate mice deficient in the inhibins have already
demonstrated the power of this approach revealing that inhibin is a novel tumor suppressor with specificity for the gonads
and the adrenal gland. Similarly, mice deficient in GDF-9 have defined it as the first oocyte-derived growth factor required
for somatic cell function in vivo. Current studies using these transgenic mice as in vivo tools will enable us to more fully
understand the relationship of these proteins in reproduction, development, and oncogenesis.
Selected Publications
Brown CW, Houston-Hawkins DE, Woodruff TK, Matzuk MM (2000) Insertion of Inhbb into the
Inhba locus rescues the Inhba-null phenotype and reveals new activin functions. Nature Genetics
25:453-457.
Cipriano SC, Chen L, Burns KH, Koff A, Matzuk MM (2001) Inhibin and p27 interact to regulate gonadal
tumorigenesis. Molecular Endocrinology 15:985-996.
Kumar TR, Varani S, Wreford NG, Telfer NM, de Kretser DM, Matzuk MM (2001) Male reproductive phenotypes in
double mutant mice lacking both FSHβ and activin receptor IIA. Endocrinology 142:3512-3518.
Varani S, Elvin JA, Yan C, DeMayo J, DeMayo FJ, Horton HF, Byrne MC, Matzuk MM (2002) Knockout of pentraxin 3, a
downstream target of growth differentiation factor-9, causes female subfertility. Molecular Endocrinology
16:1154-1167.
Yan W, Rajkovic A, Viveiros MM, Burns KH, Eppig JJ, Matzuk MM (2002) Identification of Gasz, an evolutionarily
conserved gene expressed exclusively in germ cells and encoding a protein with four ankyrin repeats, a sterile-alpha
motif, and a basic leucine zipper. Molecular Endocrinology 16:1168-1184.
Harlow CR, Davidson L, Burns KH, Yan C, Matzuk MM, Hillier SG (2002) FSH and TGF-β superfamily members
regulate granulosa cell connective tissue growth factor gene expression in vitro and in vivo. Endocrinology
143:3316-3325.
Wu X, Viveiros MM, Eppig JJ, Bai Y, Fitzpatrick SL, Matzuk MM (2003) Zygote arrest 1 (Zar1) is a novel
maternal-effect gene critical for the oocyte-to-embryo transition. Nature Genetics 33:187-191.
Burns KH, Viveiros MM, Ren Y, Wang P, DeMayo FJ, Frail DE, Eppig JJ, Matzuk MM (2003) Roles of NPM2 in chromatin
and nucleolar organization in oocytes and embryos. Science 300:633-636.
Contact Information
- Martin M. Matzuk, M.D., Ph.D.
- Department of Pathologyy
- Baylor College of Medicine
- One Baylor Plaza S217
- Houston, Texas 77030, U.S.A.
- Tel: (713) 798-6451
- Fax: (713) 798-5838
- E-mail: mmatzuk@bcm.tmc.edu
|
