RNAi knock down of the Drosophila FLCN homologue (DBHD), show that DBHD is required for germline stem cell (GSC) maintenance in the fly testis (Singh et al. 2006).

Hong et al., (2010b) found that FLCN inactivation increases the activity of TFE3 – a transcription factor that has previously been suggested to be an oncogene in renal cell carcinoma (Sidhar et al., 1996) – in BHD renal tumours compared to matched kidney tissue.

TFE3 maintains stem cell pluripotency by activating the transcription of a range of pro-pluripotency genes. Betschinger et al. (2013) showed that FLCN, together with FNIP1 and FNIP2, acts to exclude TFE3 from the nucleus, thus allowing stem cells to exit pluripotency and become poised to differentiate. FLCN’s effect on pluripotency seemed to be either downstream or independent of TSC2 and mTOR signalling (Betschinger et al., 2013).

Venables et al. (2013) showed that the FLCN interacting protein, FNIP1, is alternatively spliced during late mesoderm differentiation of fibroblasts. In primary and derived fibroblast cultures, a shorter isoform of FNIP1 lacking amino acids 208-235 predominantes, whilst in iPSCs the longer canonical form predominates. Alternative splicing of FNIP1 is controlled by MBNL1, which is required for muscle and heart development (Kalsotra et al., 2008; Lin et al., 2006).