TY - JOUR
T1 - Abnormal differentiation, hyperplasia and embryonic/perinatal lethality in BK5-T/t transgenic mice
AU - Chen, Xin
AU - Schneider-Broussard, Robin
AU - Hollowell, Debra
AU - McArthur, Mark
AU - Jeter, Collene R.
AU - Benavides, Fernando
AU - DiGiovanni, John
AU - Tang, Dean G.
N1 - Funding Information:
We thank Dr. J.J. Shen and M.B. Core for assistance in sequencing and genotyping, Dr. I. Gimenez-Conti, Ms. N. Otto, Ms. J.L. Brandon and Histology Core for IHC, and other members of the Tang lab for support and helpful discussions. This work was supported in part by grants from NIH (R01-AG023374, R01-ES015888, and R21-ES015893-01A1), American Cancer Society (RSG MGO-105961), Department of Defense (W81XWH-07-1-0616), Prostate Cancer Foundation, and Elsa Pardee Foundation (D.G.T) and by two Center Grants (CCSG-5 P30 CA166672 and ES07784). X. Chen was supported in part by a HEB predoctoral fellowship from the Department of Carcinogenesis (MDACC) and C. Jeter was supported in part by a post-doctoral fellowship from NIH and American Urological Association.
PY - 2009/3
Y1 - 2009/3
N2 - The cell-of-origin has a great impact on the types of tumors that develop and the stem/progenitor cells have long been considered main targets of malignant transformation. The SV40 (SV40-Simian Virus 40) large T and small t antigens (T/t), have been targeted to multiple-differentiated cellular compartments in transgenic mice. In most of these studies, transgenic animals develop tumors without apparent defects in animal development. In this study, we used the bovine keratin 5 (BK5) promoter to target the T/t antigens to stem/progenitor cell-containing cytokeratin 5 (CK5) cellular compartment. A transgene construct, BK5-T/t, was made and microinjected into the male pronucleus of FVB/N mouse oocytes. After implanting ∼1700 embryos, only 7 transgenics were obtained, including 4 embryos (E9.5, E13, E15, and E20) and 3 postnatal animals, which died at P1, P2, and P18, respectively. Immunohistological analysis revealed aberrant differentiation and prominent hyperplasia in several transgenic CK5 tissues, especially the upper digestive organs (tongue, oral mucosa, esophagus, and forestomach) and epidermis, the latter of which also showed focal dysplasia. Altogether, these results indicate that constitutive expression of the T/t antigens in CK5 cellular compartment results in abnormal epithelial differentiation and leads to embryonic/perinatal animal lethality.
AB - The cell-of-origin has a great impact on the types of tumors that develop and the stem/progenitor cells have long been considered main targets of malignant transformation. The SV40 (SV40-Simian Virus 40) large T and small t antigens (T/t), have been targeted to multiple-differentiated cellular compartments in transgenic mice. In most of these studies, transgenic animals develop tumors without apparent defects in animal development. In this study, we used the bovine keratin 5 (BK5) promoter to target the T/t antigens to stem/progenitor cell-containing cytokeratin 5 (CK5) cellular compartment. A transgene construct, BK5-T/t, was made and microinjected into the male pronucleus of FVB/N mouse oocytes. After implanting ∼1700 embryos, only 7 transgenics were obtained, including 4 embryos (E9.5, E13, E15, and E20) and 3 postnatal animals, which died at P1, P2, and P18, respectively. Immunohistological analysis revealed aberrant differentiation and prominent hyperplasia in several transgenic CK5 tissues, especially the upper digestive organs (tongue, oral mucosa, esophagus, and forestomach) and epidermis, the latter of which also showed focal dysplasia. Altogether, these results indicate that constitutive expression of the T/t antigens in CK5 cellular compartment results in abnormal epithelial differentiation and leads to embryonic/perinatal animal lethality.
KW - Cytokeratin 5
KW - Differentiation
KW - SV40 large T
KW - Stem cells
KW - Tongue papillae
KW - Transgenic
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U2 - 10.1016/j.diff.2008.10.011
DO - 10.1016/j.diff.2008.10.011
M3 - Article
C2 - 19272531
AN - SCOPUS:61449209888
SN - 0301-4681
VL - 77
SP - 324
EP - 334
JO - Differentiation
JF - Differentiation
IS - 3
ER -