Dynamic Expression of Axon Guidance Cues Required for Optic Tract Development Is Controlled by Fibroblast Growth Factor Signaling

Abstract

Axons are guided to their targets by molecular cues expressed in their environment. How is the presence of these cues regulated? Although some evidence indicates that morphogens establish guidance cue expression as part of their role in patterning tissues, an important question is whether morphogens are then required to maintain guidance signals. We found that fibroblast growth factor (FGF) signaling sustains the expression of two guidance cues, semaphorin3A (xsema3A) and slit1 (xslit1), throughout the period of Xenopus optic tract development. With FGF receptor inhibition, xsema3A and xslit1 levels were rapidly diminished, and retinal ganglion cell axons arrested in the mid-diencephalon, before reaching their target. Importantly, direct downregulation of XSema3A and XSlit1 mostly phenocopied this axon guidance defect. Thus, FGFs promote continued presence of specific guidance cues critical for normal optic tract development, suggesting a second later role for morphogens, independent of tissue patterning, in maintaining select cues by acting to regulate their transcription.

Heparan Sulfate Sugar Modifications Mediate the Functions ofSlitsand Other Factors Needed for Mouse Forebrain Commissure Development

“…signaling (Grobe et al, 2005) (present study) and in Xenopus FGF signaling upregulates Slit1 (but not Slit2) expression in the diencephalon (Atkinson-Leadbeater et al, 2010).…”

Development of the retina and optic pathway

“…Receding gradients of chondroitin sulfate proteoglycans (CSPGs) direct axonal growth radially toward the optic nerve head (Brittis, Canning, & Silver, 1992); cell-surface molecules promote fasciculation of later-arriving axons (Brittis & Silver, 1995; Ott, Bastmeyer, & Stuermer, 1998); Netrin signaling contributes to fiber entry into the optic stalk (Deiner, Kennedy, Fazeli, Serafini, Tessier-Lavigne & Sretavan, 1997); Slit proteins influence the positioning of optic axons as they arrive at the base of the brain (Plump, Erskine, Sabatier, Brose, Epstein, Goodman, Mason & Tessier-Lavigne, 2002); CSPGs contribute to the chronotopic reordering of optic axons as they enter the optic tract (Leung, Taylor, & Chan, 2003); and Slit and Semaphorin proteins provide directional signals further caudally within the optic tract (Atkinson-Leadbeater, Bertolesi, Hehr, Webber, Cechmanek & McFarlane, 2010). These and other factors that influence optic axonal growth and directionality have been reviewed elsewhere recently (Erskine & Thompson, 2008; Inatani, 2005; Sretavan, 2006; Xiao, Roeser, Staub & Baier, 2005).…”

Dynamic responses of Xenopus retinal ganglion cell axon growth cones to netrin‐1 as they innervate their in vivo target

“…This supports the idea that growth cones integrate multiple cues in their local environment to modulate axon elongation and branching, by differentially influencing cytoskeletal remodeling. Additional cues shown to influence RGC axon entrance into the target in vivo include fibroblast growth factor (FGF) and its signaling molecules (McFarlane et al, 1995; McFarlane et al, 1996; Atkinson-Leadbeater et al, 2010), heparin sulfate proteoglycans (Walz et al, 1997; Irie et al, 2002), Robo receptors (Plachez et al, 2008; Hocking et al, 2010), and the matrix metalloproteinase ADAM10 (Chen et al, 2007). It is therefore possible that complex molecular interactions that normally occur in the intact target are necessary for netrin-1 to differentially activate specific intracellular signaling cascades and function as a stop signal for innervating RGC axons.…”