Acosta Helena, Iliev Dobromir, Grahn Tan Hooi Min, Gouignard Nadège, Maccarana Marco, Griesbach Julia, Herzmann Svende, Sagha Mohsen, Climent Maria, Pera Edgar M
Lund Stem Cell Center, Lund University, Lund 221 84, Sweden.
Department of Experimental Medical Science, Lund University, Lund 221 84, Sweden.
Development. 2015 Mar 15;142(6):1146-58. doi: 10.1242/dev.113886.
Germ layer formation and primary axis development rely on Fibroblast growth factors (FGFs). In Xenopus, the secreted serine protease HtrA1 induces mesoderm and posterior trunk/tail structures by facilitating the spread of FGF signals. Here, we show that the serpin Protease nexin-1 (PN1) is transcriptionally activated by FGF signals, suppresses mesoderm and promotes head development in mRNA-injected embryos. An antisense morpholino oligonucleotide against PN1 has the opposite effect and inhibits ectodermal fate. However, ectoderm and anterior head structures can be restored in PN1-depleted embryos when HtrA1 and FGF receptor activities are diminished, indicating that FGF signals negatively regulate their formation. We show that PN1 binds to and inhibits HtrA1, prevents degradation of the proteoglycan Syndecan 4 and restricts paracrine FGF/Erk signaling. Our data suggest that PN1 is a negative-feedback regulator of FGF signaling and has important roles in ectoderm and head development.
胚层形成和原始轴发育依赖于成纤维细胞生长因子（FGFs）。在非洲爪蟾中，分泌型丝氨酸蛋白酶HtrA1通过促进FGF信号的传播来诱导中胚层和后躯干/尾部结构的形成。在此，我们表明丝氨酸蛋白酶抑制剂蛋白酶nexin-1（PN1）被FGF信号转录激活，在mRNA注射的胚胎中抑制中胚层并促进头部发育。针对PN1的反义吗啉代寡核苷酸具有相反的作用，并抑制外胚层命运。然而，当HtrA1和FGF受体活性降低时，PN1缺失的胚胎中外胚层和前头结构可以恢复，这表明FGF信号对它们的形成起负调控作用。我们表明PN1与HtrA1结合并抑制HtrA1，防止蛋白聚糖Syndecan 4的降解，并限制旁分泌FGF/Erk信号传导。我们的数据表明PN1是FGF信号的负反馈调节因子，在外胚层和头部发育中起重要作用。
