Axonal Guidance: Making Connections

How millions of axons navigate accurately toward synaptic targets during development is a long-standing question. Over decades, multiple studies have enriched our understanding of axonal pathfinding with discoveries of guidance molecules and morphogens, their receptors, and downstream signalling mechanisms. Interestingly, classification of attractive and repulsive cues can be fluid, as single guidance cues can act as both. Similarly, guidance cues can be secreted, chemotactic cues or anchored, adhesive cues. How a limited set of guidance cues generate the diversity of axonal guidance responses is not completely understood. Differential expression and surface localization of receptors, as well as crosstalk and spatiotemporal patterning of guidance cues, are extensively studied mechanisms that diversify axon guidance pathways. Posttranslational modification is a common, yet understudied mechanism of diversifying protein functions. Many proteins in axonal guidance pathways are glycoproteins and how glycosylation modulates their function to regulate axonal motility and guidance is an emerging field. In this review, we discuss major classes of glycosylation and their functions in axonal pathfinding. The glycosylation of guidance cues and guidance receptors and their functional implications in axonal outgrowth and pathfinding are discussed. New insights into current challenges and future perspectives of glycosylation pathways in neuronal development are discussed.

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Tissue-engineering approaches for axonal guidance

Brain Research Reviews ◽

10.1016/j.brainresrev.2004.11.002 ◽

2005 ◽

Vol 49 (1) ◽

pp. 48-64 ◽

Cited By ~ 91

Author(s):

Ning Zhang ◽

Honghai Yan ◽

Xuejun Wen

Keyword(s):

Tissue Engineering ◽

Axonal Guidance

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Restoration of early deficiency of axonal guidance signaling by guanxinning injection as a novel therapeutic option for acute ischemic stroke

Pharmacological Research ◽

10.1016/j.phrs.2021.105460 ◽

2021 ◽

pp. 105460

Author(s):

Guangxu Xiao ◽

Ming Lyu ◽

Zhixiong Li ◽

Linghua Cao ◽

Xinyan Liu ◽

...

Keyword(s):

Ischemic Stroke ◽

Acute Ischemic Stroke ◽

Therapeutic Option ◽

Axonal Guidance ◽

Novel Therapeutic

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Caenorhabditis elegansPlexinA, PLX-1, interacts with transmembrane semaphorins and regulates epidermal morphogenesis

Development ◽

10.1242/dev.129.9.2053 ◽

2002 ◽

Vol 129 (9) ◽

pp. 2053-2063 ◽

Cited By ~ 1

Author(s):

Takashi Fujii ◽

Fumi Nakao ◽

Yukimasa Shibata ◽

Go Shioi ◽

Eiji Kodama ◽

...

Keyword(s):

Rna Interference ◽

Morphological Changes ◽

Expression System ◽

Transmembrane Proteins ◽

Axonal Guidance ◽

Heterologous Expression System ◽

C Elegans ◽

Morphological Defects ◽

Epidermal Morphogenesis ◽

Null Mutants

The plexin family transmembrane proteins are putative receptors for semaphorins, which are implicated in the morphogenesis of animal embryos, including axonal guidance. We have generated and characterized putative null mutants of the C. elegans plexinA gene, plx-1. plx-1 mutants exhibited morphological defects: displacement of ray 1 and discontinuous alae. The epidermal precursors for the affected organs were aberrantly arranged in the mutants, and a plx-1::gfp transgene was expressed in these epidermal precursor cells as they underwent dynamic morphological changes. Suppression of C. elegans transmembrane semaphorins, Ce-Sema-1a and Ce-Sema-1b, by RNA interference caused a displacement of ray 1 similar to that of plx-1 mutants, whereas mutants for the Ce-Sema-2a/mab-20 gene, which encodes a secreted-type semaphorin, exhibited phenotypes distinct from those of plx-1 mutants. A heterologous expression system showed that Ce-Sema-1a, but not Ce-Sema-2a, physically bound to PLX-1. Our results indicate that PLX-1 functions as a receptor for transmembrane-type semaphorins, and, though Ce-Sema-2a and PLX-1 both play roles in the regulation of cellular morphology during epidermal morphogenesis, they function rather independently.

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ROLE FOR NETRIN-1 IN SENSORY AXONAL GUIDANCE IN HIGHER VERTEBRATES

FUKUSHIMA JOURNAL OF MEDICAL SCIENCE ◽

10.5387/fms.55.1 ◽

2009 ◽

Vol 55 (1) ◽

pp. 1-6 ◽

Cited By ~ 5

Author(s):

TOMOYUKI MASUDA ◽

CHIE SAKUMA ◽

HIROYUKI YAGINUMA

Keyword(s):

Axonal Guidance

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Comprehensive analysis of neuronal guidance cue expression regulation during monocyte-to-macrophage differentiation reveals post-transcriptional regulation of semaphorin7A by the RNA-binding protein quaking

Innate Immunity ◽

10.1177/1753425920966645 ◽

2020 ◽

pp. 175342592096664

Author(s):

Huayu Zhang ◽

Jurriën Prins ◽

Dianne Vreeken ◽

Barend W Florijn ◽

Ruben G de Bruin ◽

...

Keyword(s):

Rna Binding ◽

Binding Protein ◽

Rna Binding Protein ◽

Comprehensive Analysis ◽

Expression Regulation ◽

Axonal Guidance ◽

Macrophage Differentiation ◽

Monocyte Differentiation ◽

Guidance Cue ◽

Neuronal Guidance

In response to inflammatory cytokines and chemokines, monocytes differentiate into macrophages. Comprehensive analysis of gene expression regulation of neuronal guidance cue (NGC) ligands and receptors in the monocyte-to-macrophage differentiation process is not available yet. We performed transcriptome profiling in both human primary PBMCs/PBMC-derived macrophages and THP-1 cells/THP-1-macrophages using microarray or RNA sequencing methods. Pathway analysis showed that the axonal guidance pathway is significantly regulated upon monocyte differentiation. We confirmed NGC ligands and receptors which were consistently regulated, including SEMA4D, SEMA7A, NRP1, NRP2, PLXNA1 and PLXNA3. The involvement of RNA-binding protein quaking (QKI) in the regulation of NGC expression was investigated using monocytes and macrophages from a QKI haplo-insufficient patient and her healthy sibling. This revealed a positive correlation of SEMA7A expression with QKI expression. In silico analysis of 3′UTRs of NGCs proposed the competitive binding of QKI to proximal microRNA targeting sites as the mechanism of QKI-dependent regulation of SEMA7A. RNA immunoprecipitation confirmed an interaction of QKI with the 3′UTR of SEMA7A. Loss of SEMA7A resulted in monocyte differentiation towards a more anti-inflammatory macrophage. Taken together, the axonal guidance pathway is regulated during monocyte-to-macrophage differentiation, and the regulation is in line with the necessary functional adaption for the specialised role of macrophages.

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