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Conditional gene deletion mouse models

Tiffany Seagroves

Appointment Period: 1999-2000 / Grant Year: [15]

Tiffany SeagrovesThe pituitary gland consists of muliple, well-characterized, phenotypically distinct cell types that arise from a common primordium in a spatially and temporally specific fashion. The goal of our studies is to test the hypothesis that the critical role of the opposing signaling gradients ofBMP2/Shh and FGF8 is to establish specific cell phenotypes in the pituitarygland. Preliminary evidence from our laboratory indicates that this process is mediated by induced expression of specific transcription factors that will ultimately specify cell fate. In order to ascertain the developmental contribution of various transcription factors in the pituitary, traditional and conditional knockout mouse models will be used in combination with transgenic mouse models. Several lines of transgenic mice have been created that express Cre recombinase under control of various pituitary transcription factors, including P-Lim-Cre, P-Otx-Cre and alphaGSU-Cre. We are in the process of analyzing the temporal and spatial expression of Cre in these Cre-transgenic mice by crossing them to a floxed lacz reporter mouse line. Following this analysis, transgenic mice harboring floxed alleles of target genes of interest will be mated to the Cre-expressing lines to determine the effects of conditional deletion of each target gene.

SPECIAL NOTE: Dr. Seagroves' current funding at The University of Tennessee Health Science Center in Memphis includes three cancer research grants: The Maston Callison Bowld Cancer Research Fund, UTHSC; The Gerwin Cancer Research Fund; and The American Cancer Society. She has also been a past recipient of funding through The Department of Defense Breast Cancer Research Fellowship; The Susan G. Komen Breast Cancer Research Fund Fellowship; and a PHS/K22 Award - Center for Minority Biomedical Research Branch (relinquished to accept the afore-mentioned ACS award).

PUBLICATIONS (resulting from this training, and some recent ones)

Cao Y, Bonizzi G, Seagroves TN, Greten FR, Johnson RS, Schmidt, EV, Karin, M. (2001) IKKalpha provides an essential link between RANK signaling and cyclin D1 expression during mammary gland development. Cell 107: 763-75.

Seagroves TN, Ryan HE, Lu H, Wouters BG, Knapp M, Thibault P, Laderoute K, Johnson RS. (2001) Transcription factor HIF-1 is a necessary mediator of the pasteur effect in mammalian cells. Mol Cell Biol. 21:3436-44.

Seagroves TN, Hadsell D, McManaman J, Palmer C, Liao D, McNulty W, Welm B, Wagner KU, Neville M, Johnson RS. (2003) HIF1alpha is a critical regulator of secretory differentiation and activation, but not vascular expansion, in the mouse mammary gland. Development. 130:1713-24.

Reiter LT, Seagroves TN, Bowers M, Bier E. (2006) Expression of the Rho-GEF Pbl/ECT2 is regulated by the UBE3A E3 ubiquitin ligase. Human Molecular Genetics 15(18): 2825-2835.

Liao D, Corle C, Seagroves TN, Johnson RS. (2007) Hypoxia-inducible factor-1alpha is a key regulator of metastasis in a transgenic model of cancer initiation and progression. Cancer Res. 67:563-72.