Abstract
Tightly controlled concentration gradients of morphogens provide positional information and thus regulate tissue differentiation and morphogenesis in multicellular organisms. However, how such morphogenetic fields are formed and maintained remains debated. Here we show that fibroblast growth factor 8 (Fgf8) morphogen gradients in zebrafish embryos are established and maintained by two essential mechanisms. Firstly, Fgf8 is taken up into the cell by clathrin-mediated endocytosis. The speed of the uptake rate defines the range of the morphogenetic gradient of Fgf8. Secondly, our data demonstrate that after endocytosis the routing of Fgf8 from the early endosome to the late endosome shuts down signaling. Therefore, intracellular endocytic transport regulates the intensity and duration of Fgf8 signaling. We show that internalization of Fgf8 into the early endosome and subsequent transport towards the late endosome are two independent processes. Therefore, we hypothesize that Fgf8 receiving cells control both, the propagation width and the signal strength of the morphogen.
Highlights
The family of fibroblast growth factors (Fgfs) is currently believed to consist of 23 structurally related polypeptides controlling a wide range of biological functions [1]
Hsc70 Regulates the fibroblast growth factor 8 (Fgf8) Signaling Range To test if Clathrin-mediated Endocytosis (CME) may interfere with Fgf8 signaling, we focused on
We found that downregulation of Hsc70 expression led to an increase in the expression domain of both target genes (Fig. 1 C,I, arrows) suggesting an expanded Fgf8 signaling range
Summary
The family of fibroblast growth factors (Fgfs) is currently believed to consist of 23 structurally related polypeptides controlling a wide range of biological functions [1]. The most important roles for Fgf action are during development and regeneration when they regulate cell growth, migration, and differentiation [2,3]. They are expressed in a strict temporal and spatial pattern during embryonic differentiation and wound healing processes. Besides PLCg/protein kinase (PK)C and PI3K/Akt, Ras/MAPK is the major downstream signaling pathway activated by Fgfs, which leads to the phosphorylation of Erk [6]. Internalization and degradation of the Fgf-Fgfr complex is an important regulatory mechanism to restore basal levels of signaling
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