Spatial Fold Change of FGF Signaling Encodes Positional Information for Segmental Determination in Zebrafish

Abstract

SUMMARYSignal gradients encode instructive information for numerous decision-making processes during embryonic development. A striking example of precise, scalable tissue-level patterning is the segmentation of somites—the precursors of the vertebral column—during which the fibroblast growth factor (FGF), Wnt, and retinoic acid (RA) pathways establish spatial gradients. Despite decades of studies proposing roles for all three pathways, the dynamic feature of these gradients that encodes instructive information determining segment sizes remained elusive. We developed a non-elongating tail explant system, integrated quantitative measurements with computational modeling, and tested alternative models to show that positional information is encoded solely by spatial fold change (SFC) in FGF signal output. Neighboring cells measure SFC to accurately position the determination front and thus determine segment size. The SFC model successfully recapitulates results of spatiotemporal perturbation experiments on both explants and intact embryos, and it shows that Wnt signaling acts permissively upstream of FGF signaling and that RA gradient is dispensable.

Time and Space in Segmentation

“…In this article, I have used a simple modelling framework to explore the tissue-level consequences of in- can be partially autonomous), and also removes the expectation that the determination front should necessarily correspond with a particular signalling threshold [46].…”

“…Modelling studies provide a complementary way to interrogate segmentation processes, and have produced important conceptual advances [11,16,36,37]. Yet a range of modelling approaches with contrasting regulatory bases have been able to give more or less convincing approximations of empirical observations, and it can be unclear how to best choose between them [37][38][39][40][41][42][43][44][45][46][47][48].…”

“…Most segmentation models implicitly assume a PI framework, in which a cell moves within a PI field, continuously monitoring a graded signal, until a particular positional value induces a change in cell state [37,39,45,47,114,115]. (Other models propose that cells actually respond to a different property of the field [42,46], but the basic principle of decoding a PI signal remains the same.) An alternative hypothesis is that cells will autonomously travel along a maturation trajectory from a "posterior" state to an "anterior" state over a [100,116,117], while more anterior PSM cells will oscillate slower than posterior PSM cells in otherwise identical culture conditions [118].…”

Positional information encoded in the dynamic differences between neighbouring oscillators during vertebrate segmentation

“…How cells would sense the lack of entrainment is not known. Fgf is well known to control the somite boundary (Dubrulle et al, 2001) and recent experimental evidences in zebrafish show that the spatial difference in Fgf activity is constant at the determination front (Simzek and Özbudak, 2018). In mice, Fgf signaling activity is dynamic and has been shown to be dependent on Notch activity via Hes7 expression (Niwa et al, 2011).…”

Regulatory Network of the Scoliosis-Associated Genes Establishes Rostrocaudal Patterning of Somites in Zebrafish

“…The positions of segment boundaries are instructed by the posteroanterior gradient of fibroblast growth factor (FGF) signaling (Simsek and Ozbudak, 2018). The high FGF signal in the posterior region keeps the cell in an undifferentiated and developmentally plastic state in which the segmentation clock “ticks” (expression of clock genes oscillate) at a steady rapid rate (Pourquie, 2011).…”