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. 2000 May 23;97(11):6114-9.
doi: 10.1073/pnas.110024497.

Squamous epithelial proliferation induced by walleye dermal sarcoma retrovirus cyclin in transgenic mice

M D Lairmore  1 , J R Stanley, S A Weber, D L Holzschu
Affiliations

Squamous epithelial proliferation induced by walleye dermal sarcoma retrovirus cyclin in transgenic mice

M D Lairmore et al. Proc Natl Acad Sci U S A. .

Abstract

Walleye dermal sarcoma (WDS) is a common disease of walleye fish in the United States and Canada. These proliferative lesions are present autumn through winter and regress in the spring. Walleye dermal sarcoma virus (WDSV), a retrovirus distantly related to other members of the family Retroviridae, has been etiologically linked to the development of WDS. We have reported that the D-cyclin homologue [retroviral (rv) cyclin] encoded by WDSV rescues yeast conditionally deficient for cyclin synthesis from growth arrest and that WDSV-cyclin mRNA is present in developing tumors. These data strongly suggest that the rv-cyclin plays a central role in the development of WDS. To test the ability of the WDSV rv-cyclin to induce cell proliferation, we have generated transgenic mice expressing the rv-cyclin in squamous epithelia from the bovine keratin-5 promoter. The transgenic animals were smaller than littermates, had reduced numbers of hair follicles, and transgenic females did not lactate properly. Following injury the transgenic animals developed severe squamous epithelial hyperplasia and dysplasia with ultrastructural characteristics of neoplastic squamous epithelium. Immunocytochemistry studies demonstrated that the hyperplastic epithelium stained positive for cytokeratin and were abnormally differentiated. Furthermore, the rv-cyclin protein was detected in the thickened basal cell layers of the proliferating lesions. These data are the first to indicate that the highly divergent WDSV rv-cyclin is a very potent stimulator of eukaryotic cell proliferation and to demonstrate the potential of a cyclin homologue encoded by a retrovirus to induce hyperplastic skin lesions.

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Figures

Figure 1
Figure 1
Diagram of rv-cyclin construct (pk5svcyc) used for generation of transgenic mice. WDSV rv-cyclin was PCR amplified from the full-length plasmid clone pDL1, cut with NotI and NheI, and cloned into pBS K5 197, kindly provided by Claudio Conti (21): β-globin, β-globin + β-globin intron 2; rv-cyclin, WDSV rv-cyclin; poly(A), poly(A) additional sequences.
Figure 2
Figure 2
(A) Runting and alopecia exhibited by mouse 96 (F2 progeny from line 29) transgenic for rv-cylin compared with normal sibling mouse 216 (line 29). (B) Mouse 249 (F2 progeny from line 29) illustrating runting, generalized alopecia, and extensive epithelial thickening along tail. Inset (B): Epithelial proliferation of the tail of mouse 249. Note proliferative skin lesion with ulceration at site of tail cropping.
Figure 3
Figure 3
Microscopic lesions (hyperplasia and dysplasia) in rv-cylin transgenic mice. (A) Cross section of pinna of ear from mouse 274 (line 150) transgenic for rv-cylin illustrating marked epithelial proliferation (hyperplasia and dysplasia). Inset (A): Normal pinna of ear from mouse 216 (line 29) (×40, H&E stain). (B) Skin section from tail of mouse 274 (line 150) with severe dysplastic epithelium with altered epithelial cell layer organization and hyperkeratosis (×200, H&E stain). (C) Skin section from tail of mouse 274 (line 150) with thickened epithelium, hyperkeratosis, and epithelial layer invasion into dermis (arrow). Inset (C): Normal skin section from tail of mouse 216 (line 29) (×100, H&E stain). (D) Higher magnification of dermal invasion by epithelium from tail of mouse 274 (line 150) illustrated in C (arrow) (×200, H&E stain).
Figure 4
Figure 4
Ultrastructure of skin lesions from rv-cylin transgenic mice. (A and B) Skin sections from tail lesions from mouse 70 (line 29) illustrating pleomorphic epithelium with prominent tonofilaments, interdigitating plasma membrane extensions (A), and large and irregular nucleolar morphology (B). Cells with features of apoptotic cell death (small compact nuclei with dark condensed nuclear chromatin indicated by arrow in A). (C) Basement membranes (black arrow) disrupted by cytoplasmic extensions of epithelial cells (white arrow) from tail lesions from mouse 70 (line 29). (D) Nests of epithelial cells in a whorl pattern with convoluted nuclei from tail skin lesions from mouse 274 (line 150).
Figure 5
Figure 5
Immunohistochemical staining of hyperplastic and dysplastic epithelium from rv-cylin transgenic mice. (A) rv-Cyclin expression (arrow) in basal epithelial cells in tail skin lesion from mouse 274 (line 150) (×40). (Inset) Tail skin of normal sibling. (B) Epidermal cells from both transgenic and normal siblings (inset) illustrating diffuse cytokeratin staining (arrows in B and arrowhead in inset). (C and D) Involucrin staining with H&E counterstain illustrating atypical squamous epithelial differentiation in hyperplastic (C, ×200) and dysplastic (D, ×100) skin lesion from mouse 274 (line 150). Skin sections from normal siblings exhibited normal involucrin staining in superficial layers of epidermis (C, inset, ×200).
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