Gene expression profiles of mouse submandibular gland development: FGFR1 regulates branching morphogenesis in vitro through BMP- and FGF-dependent mechanisms
Gene expression profiles of mouse submandibular gland development: FGFR1 regulates branching morphogenesis in vitro through BMP- and FGF-dependent mechanisms
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DOI：
10.1242/dev.00172
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发表时间：
2002-12-01
期刊：
影响因子：
4.6
通讯作者：
Larsen, M
中科院分区：
文献类型：
--
作者：
Hoffman, MP;Kidder, BL;Larsen, M
分析小鼠颌下腺发育的五个不同阶段的基因表达谱有助于深入了解腺体器官发生，并识别可能在不同阶段起关键作用的基因。将表达谱相似的基因聚为一类，用RT-PCR确认发育变化。我们把重点放在成纤维细胞生长因子受体1(FGFRI)上，因为它在腺体发育的早期表达最高。我们扩展了我们的阵列结果，并分析了其他FGFR和成纤维细胞生长因子亚型的发育表达模式。颌下腺器官培养证实了FGFRI的功能意义。反义寡核苷酸减少FGFR1的表达，减少腺体的分支形态发生。用FGFR1酪氨酸激酶抑制剂SU5402抑制FGFRI信号转导，减少了分支形态的发生。SU5402处理降低细胞增殖，但不增加细胞凋亡率。用聚合酶链式反应将FGFR、成纤维细胞生长因子和骨形态发生蛋白基因定位于间充质或上皮细胞，并用实时荧光定量聚合酶链式反应检测SU5402作用后随时间的变化。FGFR1信号调节FGFR1、FGF1、Fgf3和Bmp7的表达，间接调节Fgf7、Fgf10和Bmp4的表达。在培养的腺体中加入外源FGFs和BMPs对腺体形态有明显的影响。用SU5402培养的腺体用外源性BMP7、FGF7或FGF10挽救。综上所述，我们的结果表明，特定的FGFs和BMPs在调节分支形态发生中起着相互作用，而FGFR1信号通过调节FGFs和BMP的表达而发挥核心作用。
Analyses of gene expression profiles at five different stages of mouse submandibular salivary gland development provide insight into gland organogenesis and identify genes that may be critical at different stages. Genes with similar expression profiles were clustered, and RT-PCR was used to confirm the developmental changes. We focused on fibroblast growth factor receptor 1 (FGFRI), as its expression is highest early in gland development. We extended our array results and analyzed the developmental expression patterns of other FGFR and FGF isoforms. The functional significance of FGFRI was confirmed by submandibular gland organ culture. Antisense oligonucleotides decreased expression of FGFR1 and reduced branching morphogenesis of the glands. Inhibiting FGFRI signaling with SU5402, a FGFR1 tyrosine kinase inhibitor, reduced branching morphogenesis. SU5402 treatment decreased cell proliferation but did not increase apoptosis. Fgfr, Fgf and Bmp gene expression was localized to either the mesenchyme or the epithelium by PCR, and then measured over time by real time PCR after SU5402 treatment. FGFR1 signaling regulates Fgfr1, Fgf1, Fgf3 and Bmp7 expression and indirectly regulates Fgf7, Fgf10 and Bmp4. Exogenous FGFs and BMPs added to glands in culture reveal distinct effects on gland morphology. Glands cultured with SU5402 were then rescued with exogenous BMP7, FGF7 or FGF10. Taken together, our results suggest specific FGFs and BMPs play reciprocal roles in regulating branching morphogenesis and FGFR1 signaling plays a central role by regulating both FGF and BMP expression.