Abstract
Fibroblast growth factors (FGFs) are secreted molecules that can activate the RAS/mitogen-activated protein kinase (MAPK) pathway to serve crucial functions during embryogenesis. Through an in situ hybridization screen for genes with restricted expression patterns during early zebrafish development, we identified a group of genes that exhibit similar expression patterns to FGF genes. We report the characterization of zebrafish MAP kinase phosphatase 3 (MKP3; DUSP6 - Zebrafish Information Network), a member of the FGF synexpression group, showing that it has a crucial role in the specification of axial polarity in the early zebrafish embryo. MKP3 dephosphorylates the activated form of MAPK, inhibiting the RAS/MAPK arm of the FGF signaling pathway. Gain- and loss-of-function studies reveal that MKP3 is required to limit the extent of FGF/RAS/MAPK signaling in the early embryo, and that disturbing this inhibitory pathway disrupts dorsoventral patterning at the onset of gastrulation. The earliest mkp3 expression is restricted to the future dorsal region of the embryo where it is initiated by a maternal beta-catenin signal, but soon after its initiation, mkp3 expression comes under the control of FGF signaling. Thus, mkp3 encodes a feedback attenuator of the FGF pathway, the expression of which is initiated at an early stage so as to ensure correct FGF signaling levels at the time of axial patterning.
Highlights
Fibroblast growth factors are a family of over 23 secreted glycosylated proteins that elicit a variety of important processes throughout development (Maciag and Friesel, 1995; Powers et al, 2000)
We determined that MAP kinase phosphatase 3 (MKP3) is a negative feedback regulator of Fibroblast growth factors (FGFs) signaling in the zebrafish embryo as it is in mammalian cells, and we show by loss-of-function and gainof-function experiments that MKP3 is involved in axial patterning
We show that mkp3 expression is initiated by maternal β-catenin activity prior to any detectable FGF/RAS/mitogen-activated protein kinase (MAPK) signaling
Summary
Fibroblast growth factors are a family of over 23 secreted glycosylated proteins that elicit a variety of important processes throughout development (Maciag and Friesel, 1995; Powers et al, 2000). Binding of FGFs to the FGF receptor tyrosine kinases (RTK) initiates the formation of receptor dimers resulting in the activation of the RAS/MAPK, phopholipase C gamma (PLCγ) and phosphatidylinositol 3kinase (PI3K) pathways that regulate gene transcription (Maciag and Friesel, 1995; Powers et al, 2000). FGF proteins may act in a redundant manner so that the simultaneous inactivation of multiple FGF proteins has revealed overlapping functions for these secreted ligands in several vertebrate species. Both FGF3 and FGF8 have been shown to be crucial in the formation of the zebrafish otic placode and ventral thalamus (Leger and Brand, 2002; Maroon et al, 2002; Walshe and Mason, 2003). Temporal inactivation of FGFs has revealed specific novel functions for FGF3 during the development of the posterior pharyngeal cartilage of the zebrafish ventral head skeleton (David et al, 2002)
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