Singh et al. (2006) used RNA interference to reduce the expression of the Drosophila FLCN homologue (DBHD), and showed that DBHD was required for male germline stem cell (GSC) maintenance in the fly testis. Subsequent investigation suggested that DBHD regulates GSC maintenance downstream of, or in parallel to, the JAK/STAT and Decapentaplegic (Dpp) signal-transduction pathways.

The JAK-STAT signalling cascade regulates stem cell renewal and differentiation (Harrison, 2012). Singh and Hou (2009) hypothesised that over-expression of JAK-STAT signalling results in the enlargement of the Malphigian tubules, the Drosophila equivalent of the kidneys, coupled with an increased number of proliferating cells, mitotically active cells and putative renal stem cells. Thus, aberrant JAK-STAT signalling could contribute to the renal cystic/carcinoma phenotype observed in BHD syndrome.

Dpp is the Drosophila homologue of the vertebrate bone morphogenetic proteins (BMPs), which are members of the TGF-β superfamily – a signalling system that is crucial for regulating a variety of cellular functions such as stem cell renewal (Ying et al., 2003). Three independent studies have shown that FLCN regulates TGF-β signalling: firstly, Hong et al., (2010a) used microarray analysis to show that FLCN regulates several components of the TGF-β pathway in UOK257 cells that were xenografted into nude mice. Secondly, Cash et al. (2011) observed a general loss of TGF-β mediated transcription and chromatin modifications in FLCN-null murine ES cells, and FLCN-null ES cells also failed to form normal day 12 embryoid bodies, which was also indicative of a loss of TGF-β signalling. And finally FLCN knockdown has been shown to increase TGF-β expression in HBE cells, and decrease TGF-β signalling in SAEC cells (Khabibullin et al., 2014).