170. THE ROLE OF MEGALIN IN PROSTATE DEVELOPMENT OF THE MOUSE

Abstract

Prostatic development is dependent on androgens; but the precise mechanism by which androgens mediate their effect is still unclear. Megalin, a cell membrane transporter, may shuttle sex steroids into cells to regulate androgen-responsive genes responsible for prostatic bud induction in the urogenital sinus (UGS). In megalin knockout mice, testicular descent fails and the vagina fails to open in females, both of which are dependent on sex steroid signalling (Hammes et al. 2005) . In this megalin-mediated pathway, SHBG-bound sex steroids bind to megalin, which is internalised. The SHBG-sex steroid complex is released, and the sex steroid is released from SHBG where it can bind to the androgen receptor to regulate androgen responsive genes. Receptor-Associated Protein (RAP) is a molecular chaperone protein that protects newly synthesised megalin from binding to potential ligands in the cytoplasm prior to insertion into the cell membrane. We hypothesised that megalin may shuttle SHBG-bound androgens across the cell membrane. This study characterised the expression and evaluated a possible role for megalin in the development of the mouse prostate. Megalin, SHBG and RAP transcripts were detected in the developing male and female UGS of the mouse from day E14.5 to day E18.5 (when prostatic buds start to form) and in the adult prostate. Megalin, SHBG and RAP protein were localised in the urogenital epithelium. To assess the role of megalin in prostatic development, UGS tissues were incubated with androgens in the presence and absence of RAP. Incubating UGS tissues with RAP did NOT inhibit prostatic bud initiation. Furthermore, in the UGS of megalin knockout mice, prostatic bud formation appeared to be identical to those of wild-type littermates. These results demonstrate that megalin is not involved in prostatic bud initiation. However, the ubiquitous expression of megalin suggests that its role is redundant in the prostate.

(1) Hammes A et al. (2005) Role of endocytosis in cellular uptake of sex steroids. Cell 122(5), 751–62.