Larry R. Rohrschneider
Ph.D., University of Wisconsin-Madison, Oncology, 1972.
B.S., University of Minnesota, Chemistry, 1967.
Stem cells in embryonic and adult mice with emphesis on epithelial and promordial stem cell compartments. Cancer stem cells in mammary and prostate tissue.
We have established a transgenic mouse model for stem cell analysis. The transgene in this system is GFP regulated by an internal promoter of the ship1 gene, which normally regulated expression of the N-terminal truncated protein, s-SHIP. The mouse model is designated Tg11.5kb-GFP indicating the length of the s-SHIP promoter driving GFP expression.
The s-SHIP promoter was selected because the gene product was expressed in a few stem cells and it was desired to know the full expression profile in vivo. In both transgenic mouse embryos, GFP was expressed in several epithelial stem cell compartments (skin epidermis, hair follicles, cornea, salivary glands, thymus epithelial cells) and endothelial cells (prostate). GFP was never expressed in more mature cells of the embryo.
In adult Tg11.5kb-GFP mice, we have focused on mammary tissue and the prostate. Mammary tissue exhibits two major developmental phases in the adult female, one at puberty and another during pregnancy. Both phases show temporal GFP expression in a few cells during each developmental phases, and expression shuts off upon completion of development. The GFP+ cell population has been isolated by fluorescence activated cell sorting (FACS) and stem cell activity tested by transplantation into cleared fat pads. In each case the GFP+ cells exhibited high mammary tissue outgrowth potential, whereas GFP- cells had low activity. Self-renewal of the GFP+ cells was demonstrated by serial transplantation and genetic cre/lox lineage tracing independently showed the stem cell activity of GFP+ mammary cells. These results identify mammary stem cells and allow future analytical contribution of the GFP+ cells to cancer stem cells.
Prostate tissue in Tg11.5kb-GFP male mice exhibits GFP+ cells within late embryonic development, continuing into the neonate prior to puberty. These GFP+ cells, isolated by FACS and placed in culture, grow as spheres retaining GFP+expression. Analysis of surface markers indicates that all GFP+ cells are contained within the stem cell fraction as defined by other laboratories. Transplantation experiments will begin shortly to determine whether these cells have potential for production of all mature prostate cells and structures. Together with additional experiments we will determine whether the GFP+ prostate cells are true stem cells.
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Dimerization in the grb7 protein.. Journal of molecular recognition : JMR. 25(8):427-34.. 2012.
Grb7 binds to Hax-1 and undergoes an intramolecular domain association that offers a model for Grb7 regulation.. Journal of molecular recognition : JMR. 24(2):314-21.. 2011.
s-SHIP promoter expression marks activated stem cells in developing mouse mammary tissue.. Genes & development. 24(17):1882-92.. 2010.