Facioscapulohumeral muscular dystrophy (FSHD) region gene 1 (FRG1) expression and possible function in mouse tooth germ development

Abstract

Abnormal expression of Facioscapulohumeral muscular dystrophy (FSHD) region gene 1 (FRG1) is involved in the pathogenesis of FSHD. FRG1 is also important for the normal muscular and vascular development. Our previous study showed that FRG1 is one of the highly expressed genes in the mandible on embryonic day 10.5 (E10.5) than on E12.0. In this study, we investigated the temporospatial expression pattern of FRG1 mRNA and protein during the development of the mouse lower first molar, and also evaluated the subcellular localization of the FRG1 protein in mouse dental epithelial (mDE6) cells. The FRG1 expression was identified in the dental epithelial and mesenchymal cells at the initiation and bud stages. It was detected in the inner enamel epithelium at the cap and early bell stages. At the late bell and root formation stages, these signals were detected in ameloblasts and odontoblasts during the formation of enamel and dentin matrices, respectively. The FRG1 protein was localized in the cytoplasm in the mouse tooth germ in vivo, while FRG1 was detected predominantly in the nucleus and faintly in the cytoplasm in mDE6 cells in vitro. In mDE6 cells treated with bone morphogenetic protein 4 (BMP4), the protein expression of FRG1 increased in cytoplasm, suggesting that FRG1 may translocate to the cytoplasm. These findings suggest that FRG1 is involved in the morphogenesis of the tooth germ, as well as in the formation of enamel and dentin matrices and that FRG1 may play a role in the odontogenesis in the mouse following BMP4 stimulation.

Increased FSHD region gene1 expression reduces in vitro cell migration, invasion, and angiogenesis, ex vivo supported by reduced expression in tumors

“…On the other hand, it is associated with actin bundling protein, providing structural integrity to the cell [ 13 ]. The localization of FRG1 is predominantly nuclear in cell lines such as mDEC6 and C2C12 [ 14 , 50 ]. Whereas it is predominantly cytoplasmic in, human skeletal muscle myoblasts (HSMMs), and muscle derived stem cells (MDSCs) [ 50 ].…”

“…Whereas it is predominantly cytoplasmic in, human skeletal muscle myoblasts (HSMMs), and muscle derived stem cells (MDSCs) [ 50 ]. In mDEC6 cells, BMP4 treatment of leads to change in FRG1 localization from nucleus to cytoplasm [ 14 ]. Since localization of FRG1 is critical to its function, with above-mentioned studies, we can get a clear idea that FRG1 functionality may vary amongst different systems and it depends on the activity of stromal components, as observed in animal models.…”

“…Various studies have indirectly associated FSHD with cancer. Treatment of dental epithelial cell line, mDEC6 with bone morphogenetic protein 4 (BMP4), a known tumor inhibitor, leads to translocation of FRG1 from the nucleus to the cytoplasm [ 14 ]. Moreover, FRG1’s functional domain analysis revealed that it consists of a fascin-like domain, a lipocalin domain, and two nuclear localization signals [ 11 ].…”

Reduced FRG1 expression promotes prostate cancer progression and affects prostate cancer cell migration and invasion

“…Fascin is an actin bundling protein which is known to be involved in tumor progression [7]. FRG1 is also essential for differentiation of amleoblasts, odontoblasts and matrix formation, associating it with BMP4 which is well known tumorigenesis regulator [8]. Above mentioned studies provide indications of possible involvement of FRG1 in tumorigenesis.…”

Dentinogenesis and Tooth-Alveolar Bone Complex Defects in BMP9/GDF2 Knockout Mice

“…Tooth development is regulated by sequential and reciprocal epithelium-mesenchymal interactions and their related molecular signaling [1,2]. Tooth formation is a complex process that involves many types of dental stem cells and growth and transcriptional factors, in which multiple signaling pathways converge to regulate enamel and dentin formation [3–10].…”