Where does axon guidance lead us?

Current Opinion in Neurobiology, 2002

Neuron, 1996

Neuronal growth cones navigate over long distances along specific pathways to find their correct targets. The mechanisms and molecules that direct this pathfinding are the topics of this review. Growth cones appear to be guided by at least four different mechanisms: contact attraction, chemoattraction, contact repulsion, and chemorepulsion. Evidence is accumulating that these mechanisms act simultaneously and in a coordinated manner to direct pathfinding and that they are mediated by mechanistically and evolutionarily conserved ligand-receptor systems.

Science, 1996

for helpful discussions and comments on the manuscript; and K. MacArthur and 1. Schieren for help in manuscript preparation. Work from the author's lab was supported by NIH and the Amyotrophic Lateral Sclerosis Association. T.M.J. is an Investigator of the Howard Hughes Medical Institute.

Results and problems in cell differentiation

Axons and their growth cones are specialized neuronal sub-compartments that possess translation machinery and have distinct messenger RNAs (mRNAs). Several classes of mRNAs have been identified using candidate-based, as well as unbiased genome-wide-based approaches. Axonal mRNA localization serves to regulate spatially the protein synthesis; thereby, providing axons with a high degree of functional autonomy from the soma during axon pathfinding. Importantly, de novo protein synthesis in navigating axonal growth cones is necessary for chemotropic responses to various axon guidance cues. This chapter discusses the molecular components involved in regulating axonal mRNA trafficking, targeting, and translation, and focuses on RNA binding proteins (RNBPs) and microRNAs. The functional significance of local mRNA translation in the directional response of growth cones to a gradient is highlighted along with the downstream signaling events that mediate local protein synthesis. The view that...

Development, 2006

The normal function of the nervous system requires that the constituent neurons are precisely `wired together'. During embryogenesis, each neuron extends an axonal process, which can navigate a considerable distance to its target. Although a number of the receptors and guidance signals that direct axonal growth have been identified, less is known about the transcription factors that regulate the expression of these molecules within the neuron and its environment. This review examines recent studies in vertebrates and Drosophila that address the identity of the transcription factors that either control the repertoire of guidance receptors and signals that permits an axon to take a particular trajectory or act themselves as novel extracellular guidance factors.

Neuropsychopharmacology, 2013

Nature Neuroscience, 2013

Cell adhesion molecules and diffusible cues both regulate axon pathfinding, yet how these two modes of signalling interact is poorly understood. The homophilic cell adhesion molecule, NFprotocadherin (NFPC) is expressed in the mid-dorsal optic tract neuroepithelium and in the axons of developing retinal ganglion cells (RGC). Here we report that targeted disruption of NFPC function in RGC axons or the optic tract neuroepithelium results in unexpectedly localized pathfinding defects in the mid-optic tract. Sema3A, which lies adjacent to this turn, stimulates rapid protein synthesis-dependent increases in growth cone NFPC and its cofactor, TAF1, in vitro. In vivo, growth cones exhibit marked increases in NFPC translation reporter activity in this midoptic tract region that are attenuated by blocking Neuropilin-1 function. Our results suggest that translation-linked coupling between regionally localised diffusible cues and cell adhesion can help axons navigate discrete segments of the pathway.

Current Opinion in Neurobiology, 2004

mRNA localization and regulated translation take central roles in axon guidance and synaptic plasticity. By spatially restricting gene expression within neurons, local protein synthesis provides growth cones and synapses with the capacity to autonomously regulate their structure and function. Studies in a variety of systems have provided insight into the specific roles of local protein synthesis during axonal navigation and during synaptic plasticity, and have begun to delineate the mechanisms underlying mRNA localization and regulated translation. Several powerful new tools have recently been developed to visualize each of these processes.

Current Biology, 1999

Axon guidance depends on the transduction of extracellular guidance cues into motile responses by the axonal growth cone. Recent studies in vivo have elucidated mechanisms required for this process that involve kinases and phosphatases, calcium dynamics and remodeling of the actin cytoskeleton.

Molecular Pharmacology, 2006

Axon guidance molecules, critical for neurodevelopment, are also implicated in morphological and other neurodaptative changes mediated by physiological or pharmacological events in adult brain. As an example, the psychostimulant cocaine markedly alters axon guidance molecules in adult brain of cocaine-treated rats. To decipher a potential link between drug-induced activation of G-protein-coupled receptors (GPCRs) and modulation of axon guidance molecules, we investigated whether GPCR activity in a SK-N-MC human neuroepithelioma cell line (which expresses low levels of D 1 dopamine receptors) affects gene expression of axon guidance molecules (semaphorins, ephrins, netrins, and their receptors). Using real-time polymerase chain reaction, we identified 17 of 26 axon guidance molecules in these cells, with varying levels of expression. Forskolin, which raised intracellular cAMP levels 340%, increased EphA5, EphB2, and Neuropilin1 expression, paralleling reported changes in the rat hippocampus after cocaine treatment. The dopamine receptor agonist dihydrexidine, which raised cAMP levels 22%, promoted regulatory changes in EphrinA1, EphrinA5, EphB1, DCC, and Semaphorin3C, whereas (Ϯ)-6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (SKF81297) altered EphA5, EphrinA1, EphrinA5, and neuropilin1. cAMP and other signal transduction pathways may regulate gene expression of axon guidance molecules, potentially linking monoamine receptor activation to signal transduction cascades, transcriptional regulation of axon guidance molecules, and alterations in neural networks.