Neurotrophic Factor Neurotrophin-4 Regulates Ameloblastin Expression via Full-length TrkB*
Neurotrophic Factor Neurotrophin-4 Regulates Ameloblastin Expression via Full-length TrkB*
复制标题
DOI：
10.1074/jbc.m704913200
复制
发表时间：
2008-02
影响因子：
4.8
通讯作者：
K. Yoshizaki;Shinya Yamamoto;A. Yamada;K. Yuasa;Tsutomu Iwamoto;E. Fukumoto;H. Harada;M. Saito;A. Nakasima;K. Nonaka;Yoshihiko Yamada;S. Fukumoto
中科院分区：
文献类型：
--
作者：
K. Yoshizaki;Shinya Yamamoto;A. Yamada;K. Yuasa;Tsutomu Iwamoto;E. Fukumoto;H. Harada;M. Saito;A. Nakasima;K. Nonaka;Yoshihiko Yamada;S. Fukumoto
神经营养因子不仅在神经组织和非神经组织的发育和维持中起着重要作用。几种神经营养因子在牙组织中表达，但它们在牙齿发育中的作用尚不清楚。在这里，我们报道神经营养因子神经营养因子(NT)-4促进牙上皮细胞的分化并增强牙釉质基质基因的表达。3日龄小鼠的牙上皮细胞表达NT-4和TrkB神经营养因子受体的三种变体（全长TrkB- fl和截断的TrkB- t1和-T2）。牙上皮细胞系HAT-7表达这些基因，与牙上皮细胞相似。我们发现NT-4可以降低HAT-7细胞的增殖，诱导成釉细胞素（Ambn）等釉质基质基因的表达。用TrkB-FL表达构建体转染HAT-7细胞可增强nt -4介导的Ambn表达诱导。这种增强作用被Trk酪氨酸激酶抑制剂K252a阻断。NT-4在HAT-7细胞中诱导TrkB的下游分子ERK1/2磷酸化。在nt -4处理的HAT-7细胞中，转染TrkB-FL而不转染TrkB-T1可提高ERK1/2的磷酸化水平。这些结果表明NT-4通过TrkB-MAPK途径诱导Ambn表达。p75抑制剂TAT-pep5降低了NT-4介导的Ambn、TrkB-FL和TrkB-T1表达的诱导，表明NT-4活性需要高亲和力和低亲和力的神经营养因子受体。我们发现nt -4缺失小鼠的牙釉质层变薄，Ambn表达减少。我们的研究结果表明NT-4调节牙上皮的增殖和分化，促进牙釉质基质的产生。
Neurotrophic factors play an important role in the development and maintenance of not only neural but also nonneural tissues. Several neurotrophic factors are expressed in dental tissues, but their role in tooth development is not clear. Here, we report that neurotrophic factor neurotrophin (NT)-4 promotes differentiation of dental epithelial cells and enhances the expression of enamel matrix genes. Dental epithelial cells from 3-day-old mice expressed NT-4 and three variants of TrkB receptors for neurotrophins (full-length TrkB-FL and truncated TrkB-T1 and -T2). Dental epithelial cell line HAT-7 expressed these genes, similar to those in dental epithelial cells. We found that NT-4 reduced HAT-7 cell proliferation and induced the expression of enamel matrix genes, such as ameloblastin (Ambn). Transfection of HAT-7 cells with the TrkB-FL expression construct enhanced the NT-4-mediated induction of Ambn expression. This enhancement was blocked by K252a, an inhibitor for Trk tyrosine kinases. Phosphorylation of ERK1/2, a downstream molecule of TrkB, was induced in HAT-7 cells upon NT-4 treatment. TrkB-FL but not TrkB-T1 transfection increased the phosphorylation level of ERK1/2 in NT-4-treated HAT-7 cells. These results suggest that NT-4 induced Ambn expression via the TrkB-MAPK pathway. The p75 inhibitor TAT-pep5 decreased NT-4-mediated induction of the expression of Ambn, TrkB-FL, and TrkB-T1, suggesting that both high affinity and low affinity neurotrophin receptors were required for NT-4 activity. We found that NT-4-null mice developed a thin enamel layer and had a decrease in Ambn expression. Our results suggest that NT-4 regulates proliferation and differentiation of the dental epithelium and promotes production of the enamel matrix.