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Transcriptional regulation of vertebrate axon guidance and synapse formation

Nature Reviews Neuroscience volume 8, pages 331–340 (2007)Cite this article

Key Points

  • Recent studies indicate that transcription factors have a crucial role in regulating axon guidance and synapse formation. Many of these factors act by regulating the response of neurons to guidance and synaptogenic cues.

  • Islet 2 (ISL2), ZIC2, chick brain factor 1 (CBF1) and CBF2 are transcription factors that have been implicated in retinotectal patterning. ISL2 and ZIC2 appear to exert their effects by regulating EphB2 expression. CBF1 and CBF2 seem to exert their effects by regulating ephrin A–EphA signalling.

  • ISL1, LIM1, LHX3 and LMX1B are LIM homeobox transcription factors that are implicated in the development of motor neuron projections. These factors are likely to affect axonal trajectories by influencing signalling by ephrins, semaphorins and fibroblast growth factors.

  • Neurogenin 2, LIM domain only 4 (LMO4) and neurodifferentiation D2 (NeuroD2) have an important role in patterning thalamocortical axons. LMO4 and NeuroD2 are expressed in the postnatal cortex and mediate the activity-dependent refinement of thalamocortical axon terminals.

  • Many of the transcription factors that affect axon guidance act by regulating the expression of ephrin and Eph receptor genes.

  • Several transcription factors have been implicated in synapse formation, maturation and elimination. Cyclic AMP-response element binding protein (CREB) and NeuroD2 are involved in synapse formation and maturation. Myocyte enhancer factor 2 (MEF2) and neurogenin 3 appear to be involved in synapse elimination. These factors act in part by regulating the responsiveness of neurons to neurotransmitters.

Abstract

The establishment of functional neural connections requires the growth of axons to specific target areas and the formation of synapses with appropriate synaptic partners. Several molecules that regulate axon guidance and synapse formation have been identified in the past decade, but it is unclear how a relatively limited number of factors can specify a large number of connections. Recent evidence indicates that transcription factors make a crucial contribution to the specification of connections in the nervous system by coordinating the response of neurons to guidance molecules and neurotransmitters.

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Figure 1: Transcriptional control of midline crossing by retinal axons.
Figure 2: Transcriptional regulation of the topography of retinotectal projections.
Figure 3: Regulation of thalamocortical patterning by NeuroD2 and LMO4.
Figure 4: Specification of motorneuron projections.
Figure 5: Transcription factors implicated in the regulation of synapse formation and synapse elimination.

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Authors and Affiliations

  1. Department of Pharmacology, Neuroscience Center, Neurodevelopmental Diseases Research Center, University of North Carolina, Chapel Hill, 27599-7250, North Carolina, USA

    Franck Polleux

  2. Laboratory of Molecular Neuro-Oncology, The Rockefeller University, 1230 York Avenue, BOX 226, New York, 10021, USA

    Gulayse Ince-Dunn

  3. Division of Biological Sciences, Neurobiology Section, University of California San Diego, La Jolla, 92093-0366, California, USA

    Anirvan Ghosh

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Correspondence to Anirvan Ghosh.

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FURTHER INFORMATION

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Glossary

Zinc-finger transcription factor

A protein motif consisting of two antiparallel β-strands and an α-helix forming a binding pocket for a zinc ion that is crucial for the stability of this domain type.

LIM homeodomain transcription factor

A subclass of homeodomain transcription factors consisting of a zinc-binding motif that mediates protein–protein interaction.

Winged-helix transcription factor

Also called forkhead (or FOX). A class of transcription factors characterized by a 100-amino-acid, monomeric DNA-binding domain that folds into a variant of the helix-turn-helix motif and is made up of three α-helices and two characteristic large loops, or 'wings'.

Retinal waves

Waves of spontaneous neural activity generated partly by the bursting of retinal ganglion cells (RGC) and propagating throughout the retina. This correlated, spontaneous activity is conveyed to the lateral geniculate nucleus (LGN) and the visual cortex and is necessary for the segregation of eye-specific layers within the LGN, and the refinement of retinotopy.

Inter-areal topography

The topography of projection of axons originating from a thalamic nucleus to a specific set of cortical areas.

Intra-areal topography

The topography of projection of axons from one thalamic nucleus inside a given cortical area.

Basic helix-loop-helix

(bHLH). Approximately 15 charged residues (basic domain) conferring specificity of DNA binding as well as a helix-loop-helix motif mostly involved in dimerization.

Barrel cortex

The part of the rodent somatosensory cortex that receives sensory input from contralateral whisker follicles. The barrel cortex has been a useful model system to study cortical connections because of the ease with which anatomical representations of thalamocortical axon terminals can be visualized.

Transcriptional co-activator

A protein factor which on recruitment to a specific promoter activates gene transcription. Co-activators do not directly bind to DNA but are associated with transcription-factor complexes.

Fluorescence-activated cell sorting

(FACS). A technique that can rapidly separate cells in a suspension on the basis of their size and their fluorescence.

Transcription profiling

Genome-wide analysis of mRNA transcript expression in groups of cells using DNA microarray hybridization technology.

Small hairpin RNA

A sequence of RNA that makes a tight hairpin turn and can be used to silence gene expression in mammalian cells.

Hox transcription factors

A subgroup of homeobox genes that are found in a special gene cluster, the Hox cluster (also called Hox complex). There are four classes (A to D) of Hox genes that function in patterning the body axis, including the CNS.

Dermomyotome

A transitory epithelial sheet of cells formed during somite maturation. The dermomyotome is the source of most of the mesodermal tissues in the body, giving rise to cell types as diverse as muscle, connective tissue, endothelium and cartilage.

Plexus

A network of intersecting nerves.

Silent synapses

Excitatory glutamatergic synapses that contain NMDA (N-methyl-D-aspartate)-type but no AMPA (α-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid)-type glutamate receptors and as a result do not respond to stimulation at resting membrane potentials.

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Polleux, F., Ince-Dunn, G. & Ghosh, A. Transcriptional regulation of vertebrate axon guidance and synapse formation. Nat Rev Neurosci 8, 331–340 (2007). https://doi.org/10.1038/nrn2118

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