The formation of morphogen gradients is of fundamental importance in biology. Fibroblast growth factors (FGFs) have key functions in embryonic development and the adult, yet little is known about how the distribution and strength of these signals is regulated in the extracellular space. Recently we demonstrated that the secreted serine protease xHtrA1 promotes long-range FGF signaling through mobilizing FGF-proteoglycan complexes during germ layer development and the establishment of the body plan (Hou et al. 2007. Dev. Cell 13, 1-16). Here we introduce the secreted serine protease inhibitor SPI as a specific antagonist of the xHtrA1-FGF axis. SPI is expressed and transcriptionally activated by FGF signals in the early Xenopus embryo. Microinjection of SPI mRNA promotes antero-dorsal development. In contrast, antisense morpholino oligonucleotides against SPI cause loss of head and enlargement of ventro-posterior structures. SPI binds to xHtrA1 and blocks xHtrA1-induced secondary tail formation, mesoderm induction and neuronal differentiation. SPI also blocks endogenous and xHtrA1-induced activation of the FGF signaling intermediate Erk1/2. Our results suggest that SPI is a negative feedback regulator of FGF signals and adds another layer to the extracellular regulation of xHtrA1-FGF activity in the embryo
