Flcn-flox Mouse

Flcn, encoding folliculin, is a tumor suppressor gene. Although its encoded protein has no sequence homology to known functional domains, the C-terminus of FLCN shows structural similarity to DENN domain proteins. FLCN is involved in diverse metabolic pathways and cellular processes, such as modulating the mTOR pathway, regulating PGC1α and mitochondrial biogenesis, cell-cell adhesion, RhoA signaling, controlling TFE3/TFEB transcriptional activity, amino-acid-dependent activation of mTORC1 on lysosomes, and regulating autophagy. Mutations in Flcn are responsible for Birt-Hogg-Dubé (BHD) syndrome, which predisposes to fibrofolliculomas, lung cysts, spontaneous pneumothorax, and an increased risk of kidney tumors [1].

In hematopoietic-lineage-specific Flcn-knockout mice, vacuolated phagocytes accumulate glycogen in their cytoplasm, resembling lysosomal storage disorder. TFE3, a master transcription factor for lysosomal biogenesis, acts in a feedback loop to transcriptionally activate Flcn expression. Loss of Flcn disrupts this loop, augmenting TFE3 activity. Deletion of Tfe3 in Flcn knockout mice reduces the number of phagocytes and ameliorates the LSD-like phenotypes. This indicates that the FLCN-TFE3 feedback loop controls lysosome activity and prevents excessive glycogenesis and phagocyte activation [2].

In conclusion, Flcn is crucial for regulating multiple biological processes through its involvement in various pathways. The study of Flcn-knockout mouse models has provided valuable insights into its role in BHD syndrome-associated phenotypes, such as the abnormal cellular phenotypes related to lysosomal function and glycogen metabolism. This helps in understanding the disease mechanisms and potentially developing targeted therapies for BHD-related disorders.