Generation Of Epidermal Specific Flcn Knockout Mice And Investigation Of The Relationship Between FLCN And NF-κB

The BHD（Birt-Hogg-Dubé）syndrome is a genetic disorder caused by mutations of the tumor suppressor gene folliculin（Flcn）.Most of the BHD patients suffer from fibrofolliculoma,which is a benign hair follicle tumor.In order to dissect the FLCN functions in the skin,this research generated a new conditional Flcn knockout mouse model.In this model,two Lox P sequences were inserted outside of the 5-6 exons of the Flcn gene.The epidermis specific Flcn knockout mice were obtained using the Cre-Lox P system（with the Keratin14-Cre driver）.With the combination of histology,molecular biology and cell biology techniques,this study examined the phenotypes of epidermis-Flcn knockout mice and revealed that loss of FLCN activated NF-κB.The main findings are as follows:1.A new Flcn^flox/flox transgenic mouse model was successfully constructed.Homozygous mice are healthy and fertile.2.The epidermis specific Flcn knockout mice showed the following phenotypes:slow groth rate,small body size,delayed opening of eyelid,curved whiskers,rough hair and hair loss,skin redness,some portions of skin had melanin deposition,thickened epidermis;3.In the Flcn-deficient mouse epidermis,the NF-κB singnaling pathway is activated and the expression of certain NF-κB downstream inflammatory cytokines are increased;Similar results were obtained in Flcn-deficient human kidney HEK293T cells.Inhibition of NF-κB reduced the expression of inflammatory cytokines in Flcn-deficient HEK293T cells.In summary,a new Flcn conditional knockout mouse model was obtained.The NF-κB signaling pathway is activated after FLCN loss in both mouse epidermis and human HEK293T cells.This study provides a new mouse model to study the mechnisms of BHD and suggests that abnormal actiation of NF-κB might contributes to some BHD abnormalities.