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eNeuro 2019 Apr 09;62:. doi: 10.1523/ENEURO.0086-19.2019.
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The Expression of Key Guidance Genes at a Forebrain Axon Turning Point Is Maintained by Distinct Fgfr Isoforms but a Common Downstream Signal Transduction Mechanism.

Yang JJ , Bertolesi GE , Dueck S , Hehr CL , McFarlane S .

During development the axons of neurons grow toward and locate their synaptic partners to form functional neural circuits. Axons do so by reading a map of guidance cues expressed by surrounding tissues. Guidance cues are expressed at a precise space and time, but how guidance cue expression is regulated, and in a coordinated manner, is poorly understood. Semaphorins (Semas) and Slits are families of molecular ligands that guide axons. We showed previously that fibroblast growth factor (Fgf) signaling maintains sema3a and slit1 forebrain expression in Xenopus laevis, and these two repellents cooperate to guide retinal ganglion cell (RGC) axons away from the mid-diencephalon and on towards the optic tectum. Here, we investigate whether there are common features of the regulatory pathways that control the expression of these two guidance cues at this single axon guidance decision point. We isolated the sema3a proximal promoter and confirmed its responsiveness to Fgf signaling. Through misexpression of truncated Fgf receptors (Fgfrs), we found that sema3a forebrain expression is dependent on Fgfr2-4 but not Fgfr1. This is in contrast to slit1, whose expression we showed previously depends on Fgfr1 but not Fgfr2-4. Using pharmacological inhibitors and misexpression of constitutively active (CA) and dominant negative (DN) signaling intermediates, we find that while distinct Fgfrs regulate these two guidance genes, intracellular signaling downstream of Fgfrs appears to converge along the phosphoinositol 3-kinase (PI3K)-Akt signaling pathway. A common PI3K-Akt signaling pathway may allow for the coordinated expression of guidance cues that cooperate to direct axons at a guidance choice point.

PubMed ID: 30993182
PMC ID: PMC6464512
Article link: eNeuro

Species referenced: Xenopus laevis
Genes referenced: actb akt1 dynll1 fgfr1 fgfr2 fgfr3 fgfr4 gab1 grb2 hpse map3k1 mapk1 myc pik3ca pik3cg sdc2 sema3a slit1 slit2 spry1 tec tubb
GO keywords: axon guidance [+]
Antibodies: Akt Ab10 Gapdh Ab4 Mapk1 Ab7 Sema3a Ab1

Article Images: [+] show captions
References [+] :
Aksamitiene, Cross-talk between mitogenic Ras/MAPK and survival PI3K/Akt pathways: a fine balance. 2012, Pubmed