Abstract
Tooth development is initiated by epithelial-mesenchymal interactions via basement membrane (BM) and growth factors. In the present study, we found that nephronectin (Npnt), a component of the BM, is highly expressed in the developing tooth. Npnt localizes in the BM on the buccal side of the tooth germ and shows an expression pattern opposite that of the dental epithelial stem cell marker Sox2. To identify the roles of Npnt during tooth development, we performed knockdown and overexpression experiments using ex vivo organ and dental epithelial cell cultures. Our findings showed that loss of Npnt induced ectopic Sox2-positive cells and reduced tooth germ size. Over expression of Npnt showed increased proliferation, whereas the number of Sox2-positive cells was decreased in dental epithelial cells. Npnt contains 5 EGF-like repeat domains, as well as an RGD sequence and MAM domain. We found that the EGF-like repeats are critical for Sox2 expression and cell proliferation. Furthermore, Npnt activated the EGF receptor (EGFR) via the EGF-like repeat domains and induced the PI3K-Akt signaling pathway. Our results indicate that Npnt plays a critical scaffold role in dental epithelial stem cell differentiation and proliferation, and regulates Sox2 expression during tooth development.
Highlights
The basement membrane (BM), a sheet-like extracellular matrix, lies between epithelium and mesenchyme, and plays important roles in organogenesis by regulating signals for cell proliferation, migration, and differentiation[9,10]
We found that Npnt plays critical roles in dental epithelial stem cell differentiation via regulation of Sox[2] expression via the EGF signaling pathway through its EGF-like repeat domains
To elucidate the expression pattern of Npnt during tooth development, we performed quantitative RT-PCR assays using total RNA from tooth, skin, lung, liver, kidney heart eye, and brain samples obtained on E14 and from teeth at various developmental stages [E11, E13, E14, E15, E16, E18, postnatal day 0 (P0), P3, P7]
Summary
Sox[2] expression and proliferation in dental epithelial stem cells via received: 19 January 2017 accepted: 17 February 2017. Our results indicate that Npnt plays a critical scaffold role in dental epithelial stem cell differentiation and proliferation, and regulates Sox[2] expression during tooth development. The basement membrane (BM), a sheet-like extracellular matrix, lies between epithelium and mesenchyme, and plays important roles in organogenesis by regulating signals for cell proliferation, migration, and differentiation[9,10]. Nephronectin (Npnt), an ECM protein possessing 5 EGF-like repeat domains, as well as an RGD sequence and COOH-terminal MAM domain, localizes in the BM of developing organs, such as the eyes, lungs, teeth, hair, taste buds, and kidneys[15]. We found that Npnt plays critical roles in dental epithelial stem cell differentiation via regulation of Sox[2] expression via the EGF signaling pathway through its EGF-like repeat domains
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