The Drosophila homolog of the human tumor suppressor gene BHD interacts with the JAK-STAT and Dpp signaling pathways in regulating male germline stem cell maintenance

Birt–Hogg–Dubé syndrome (BHD) is a rare, inherited genodermatosis characterized by hair follicle hamartomas, kidney tumors and spontaneous pneumothorax. The BHD locus was mapped to chromosome 17p11.2 by linkage analysis, and germline mutations in a novel gene ( BHD ) were identified in a panel of BHD families. Using RNA interference to decrease expression of the Drosophila BHD homolog ( DBHD ), we have demonstrated that DBHD is required for male germline stem cell (GSC) maintenance in the fly testis. Reduction of DBHD gene activity suppresses the GSC overproliferation phenotype associated with overexpression of either unpaired ( upd ) or decapentaplegic ( dpp ). Further genetic interaction experiments suggest that DBHD regulates GSC maintenance downstream or in parallel of the JAK/STAT and Dpp signal-transduction pathways. These findings suggest that the BHD protein may regulate tumorigenesis through modulating stem cells in human.