ORIGIN OF TESTICULAR TUMORS IN TRANSGENIC MICE OBTAINED BY TARGETED ONCOGENESIS USING AN AMH PROMOTER/SIMIAN VIRUS 40 T ANTIGEN (SV40T) FUSION CONSTRUCT

QUINTANA S., VENARA M. , REY R., CHEMES H.

Buenos Aires, Argentina

Jornada; VIII Jornadas Multidisciplinarias de la Sociedad Argentina de Biología; 2006

Sociedad Argentina de Biología

Transgenic mice bearing a construct in which the SV40T expression is directed by the Antimullerian Hormone (AMH) promoter (AT mice) develop testicular tumors in adult life. These tumors are preceded by interstitial hyperplasia and microtumors. Their phenotype indicates a mixed Leydig-Sertoli differentiation.  Our aim was to study the cellular origin of these tumors by immunohistochemical localization of SV40T, AMH and  3b-ƒnhydroxysteroid dehydrogenase (3b-HSD) in fetal (12,5 and 14,5 dpc) and postnatal (3-15 day-old) mice. No tumors or hyperplasia were seen in control mice, and SV40T was always negative. 3b-HSD was positive in all Leydig cells of control and AT mice. AMH expression was intense in Sertoli cells until 7 days and progressively diminished to disappear at 15 days in control  and AT mice. This very same pattern and chronology of expression was observed for SV40T in AT Sertoli cells, which is compatible with the normal postnatal downregulation of the AMH promoter. SV40T was also expressed in focal hyperplasias in the interstitium of all postnatal AT mice where it colocalized with 3b-HSD indicating their Leydig cell origin. The unexpected finding that an oncogen directed by a promoter specifically active in Sertoli cells has given rise to testicular tumors with Leydig differentiation is compatible with the origin of Leydig and Sertoli cells from a common precursor in the specific stroma of the gonadal ridge. These results would indicate that Leydig cells, transformed by the presence of the oncogen, give rise to tumors because they lack the mechanisms of AMH promoter downregulation that normally operates in postnatal Sertoli cells.