Abstract
Gradients of signaling proteins are essential for inducing tissue morphogenesis. However, mechanisms of gradient formation remain controversial. Here we characterized the distribution of fluorescently-tagged signaling proteins, FGF and FGFR, expressed at physiological levels from the genomic knock-in alleles in Drosophila. FGF produced in the larval wing imaginal-disc moves to the air-sac-primordium (ASP) through FGFR-containing cytonemes that extend from the ASP to contact the wing-disc source. The number of FGF-receiving cytonemes extended by ASP cells decreases gradually with increasing distance from the source, generating a recipient-specific FGF gradient. Acting as a morphogen in the ASP, FGF activates concentration-dependent gene expression, inducing pointed-P1 at higher and cut at lower levels. The transcription-factors Pointed-P1 and Cut antagonize each other and differentially regulate formation of FGFR-containing cytonemes, creating regions with higher-to-lower numbers of FGF-receiving cytonemes. These results reveal a robust mechanism where morphogens self-generate precise tissue-specific gradient contours through feedback regulation of cytoneme-mediated dispersion.
Highlights
Diverse tissue shapes and patterns are created by conserved paracrine signaling proteins such as Transforming Growth Factor b (TGFb), Hedgehog (Hh), Wingless (Wg/WNT), Epidermal Growth Factor (EGF) and Fibroblast growth factor (FGF)
We aimed to address these fundamental questions by characterizing gradient formation of a Drosophila FGF family protein, Branchless (Bnl)
A strong negative correlation of the gradient slopes with the length of the ASP D-P axis was observed in a population of randomly harvested wandering third instar larval ASPs, which showed natural developmental variations in size (Figure 1H). These results showed that the range and slope of the Bnl:GFP gradients are dependent on the ASP morphology and that the gradient did not preexist, but instead developed dynamically in coordination with the recipient tissue morphogenesis
Summary
Diverse tissue shapes and patterns are created by conserved paracrine signaling proteins such as Transforming Growth Factor b (TGFb), Hedgehog (Hh), Wingless (Wg/WNT), Epidermal Growth Factor (EGF) and Fibroblast growth factor (FGF). Irrespective of the diversity of the functions and forms created, a universal mode by which these signals coordinate responses in a large population of cells involves the generation of concentration gradients. Morphogen gradients induce concentration-dependent gene activities that regulate tissue growth and patterning (reviewed in (Bier and De Robertis, 2015; Christian, 2012; Restrepo et al, 2014; Rogers and Schier, 2011; Wolpert, 2016)). Growth factor and chemokine gradients are thought to control cell migration during vasculogenesis, neurogenesis, wound healing, and immune responses (Cai and Montell, 2014; Majumdar et al, 2014). The formation of signal gradients is unexplored in most morphogenetic contexts, so we do not know how dispersion of the signals through extracellular space can generate the required diversity in gradient shapes and contours for a multitude of tissue architectures
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