Testis

The Helix-Loop-Helix Inhibitor of Differentiation Proteins Induce Post-Mitotic Terminally Differentiated Sertoli Cells to Re-Enter the Cell Cycle and Proliferate

Abstract
Prior to puberty the Sertoli cells undergo active cell proliferation and at the onset of puberty become a terminally differentiated post-mitotic cell population to support spermatogenesis. The molecular mechanisms involved in the post-mitotic block of pubertal and adult Sertoli cells is unknown. The four known helix-loop-helix ID proteins (i.e. Id1, Id2, Id3, and Id4) are considered dominant negative regulators of cellular differentiation pathways and act as positive regulators of cellular proliferation. ID proteins are expressed at low levels by post-pubertal Sertoli cells and are transiently induced by serum. The hypothesis tested was that ID proteins can induce a terminally differentiated post-mitotic Sertoli cell to re-enter the cell cycle if constitutively expressed. In order to test this hypothesis, ID1 and ID2 were stably integrated and individually over-expressed in post mitotic rat Sertoli cells. Over-expression of ID1 or ID2 allowed the post-mitotic Sertoli cells to re-enter the cell cycle and undergo mitosis. The cells continue to proliferate even after 300 cell doublings. The functional markers of Sertoli cell differentiation such as transferrin, inhibin alpha, Sert-1 and androgen binding protein (ABP) continued to be expressed by the proliferating Sertoli cells, but at lower levels. FSH receptor expression was lost in the proliferating Sertoli cell-Id lines. Some Sertoli cell genes such as cyclic protein 2 (cathepsin L) and Sry Related HMG box protein-11 (Sox11) increase in expression. At no stage of proliferation did the cells exhibit senescence. The expression profile, as determined with a microarray protocol, of the Sertoli cell-Id lines suggested an overall increase in cell cycle genes and decrease in growth inhibitory genes. These results demonstrate that over-expression of ID1 and ID2 genes in a post-mitotic terminally differentiated cell type has the capacity to induce re-entry into the cell cycle. The observations are discussed in regards to potential future applications in model systems of terminally differentiated cell types such as neurons or myocytes.

Key words: Testis • Sertoli cells

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