Abstract
The guidance receptor DCC (deleted in colorectal cancer) ortholog UNC-40 regulates neuronal asymmetry development in Caenorhabditis elegans, but it is not known whether DCC plays a role in the specification of neuronal polarity in vertebrates. To examine the roles of DCC in neuronal asymmetry regulation in vertebrates, we studied zebrafish anterior dorsal telencephalon (ADt) neuronal axons. We generated transgenic zebrafish animals expressing the photo-convertible fluorescent protein Kaede in ADt neurons and then photo-converted Kaede to label specifically the ADt neuron axons. We found that ADt axons normally project ventrally. Knock down of Dcc function by injecting antisense morpholino oligonucleotides caused the ADt neurons to project axons dorsally. To examine the axon projection pattern of individual ADt neurons, we labeled single ADt neurons using a forebrain-specific promoter to drive fluorescent protein expression. We found that individual ADt neurons projected axons dorsally or formed multiple processes after morpholino knock down of Dcc function. We further found that knock down of the Dcc ligand, Netrin1, also caused ADt neurons to project axons dorsally. Knockdown of Neogenin1, a guidance receptor closely related to Dcc, enhanced the formation of aberrant dorsal axons in embryos injected with Dcc morpholino. These experiments provide the first evidence that Dcc regulates polarized axon initiation and asymmetric outgrowth of forebrain neurons in vertebrates.
Highlights
IntroductionIn unc-40 loss of function mutants or in unc-40 missense plus unc-6 double mutants, hermaphrodite specific neurons (HSN) axons extend anteriorly, posteriorly, or dorsally, instead of towards the correct ventral position [15]
Co-injection of the sub-threshold concentrations of dcc-MO and ntn-MO together resulted in the formation of significant number of aberrant dorsal axons (42.163.7% of embryos, n = 61; ANOVA, F2, 6 = 52.31, p = 1.6061024, Fig. 5C). These results indicated that Dcc and Netrin1 genetically interacted to determine the asymmetric outgrowth of the anterior dorsal telencephalon (ADt) neuronal axons
Outgrowth of Forebrain Neuronal Axons Our studies demonstrate that Dcc signaling plays a central role in asymmetric outgrowth of ADt neuronal axons in the zebrafish forebrain
Summary
In unc-40 loss of function mutants or in unc-40 missense plus unc-6 double mutants, HSN axons extend anteriorly, posteriorly, or dorsally, instead of towards the correct ventral position [15]. These studies suggest that the guidance receptor DCC is a key regulator of neuronal asymmetry in C. elegans. The functions of DCC in axon guidance and cell migration are conserved in bilateria [16,17,18,19], but few studies have examined the roles of DCC in neuronal polarity regulation in vertebrates
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