Further tales of the midline

https://doi.org/10.1016/j.conb.2010.07.008Get rights and content

In the vertebrate central nervous system (CNS), specialized glial and neuronal cells positioned at the dorsal and ventral midline act as intermediate targets for commissural axons by secreting a variety of attractants and repellents. Despite the diversity of commissural projections, recent findings suggest that the same basic set of molecules controls midline crossing at all level of the CNS. Midline crossing is associated with an important switch of the combinatorial expression of several axon guidance receptors on the growth cone of commissural axons. I will review here novel studies that reveal how the expression of these receptors and the activity of their ligands are modulated by transcriptional, translational, and post-translational modifications. This also uncovers extensive cross talks between axon guidance pathways.

Introduction

From the spinal cord to the base of the olfactory bulb, millions of commissural neurons project their axon across the midline and are essential for the integration of sensory information and for eliciting proper motor and sensory motor behaviors [1]. In the forebrain, commissural axons cross the midline at specific and restricted locations such as the anterior and posterior commissures or the corpus callosum, each of which gathers axons originating from various regions. For instance, the anterior commissure includes axons from the amygdala, anterior olfactory nucleus, and cortex, while the corpus callosum is a heterogeneous collection of axons from cortical layers II/III and V/VI. In the hindbrain and spinal cord, there exists a higher diversity of commissural neurons that cross the midline at all levels, rarely forming well defined tracts. Despite this apparent heterogeneity, the past two decades have revealed that the molecular mechanisms controlling midline crossing in the CNS are highly similar and that the same basic set of attractive and repulsive cues are used throughout developing brains. In the past two years there has been a decrease in the discovery of new axon guidance molecules, but in the meantime, there has been considerable progress made in assembling the molecular pieces of the midline guidance puzzle.

I will discuss here the current understanding of the molecular mechanisms underlying midline crossing in the vertebrate brain, taking the corpus callosum and spinal cord as model systems. In both cases new findings confirmed that semaphorins are key players at the midline acting as repellents or attractants and also started to reveal how their activity is modulated in commissural axons. I will end reviewing a series of studies that provide new insights into the transcriptional and translational regulation of the expression of axon guidance receptors.

Section snippets

Crossing the corpus callosum

In eutherians, the two hemispheres are connected by callosal axons that establish reciprocal connections between cortical areas processing similar information. Although it is estimated that the corpus callosum contains about half of all commissural axons, its ablation, performed in ‘split-brain’ patients, or its absence in a variety/large number of mutant mice does not clearly result in major disorders of brain function [2, 3]. Still, the corpus callosum has become a major model system for

Semaphorin 6A and the secret of the pyramids

The corticospinal tract (CST) connects layer V pyramidal neurons, primarily from the motor cortex, to their target neurons (mostly interneurons) in the spinal cord [17]. CST axons grow ipsilaterally through the internal capsule, cerebral peduncle, and midbrain and penetrate the hindbrain ventrally, over the pons. CST axons next follow a ventral trajectory passing beneath the inferior olive where they abruptly reorient dorsally and cross the midline, forming the pyramidal decussation, before

The semaphorin double switch

One of the most challenging questions in the field is to understand how commissural axons switch from midline attraction to repulsion. In vertebrates, a first step seems to be the silencing of Netrin1 attraction triggered by the binding of Robo1 receptor to DCC in the presence of Slit (Figure 2) [23]. Secondly, stem cell factor (SCF) released by the floor plate is required to expel commissural axons expressing its receptor Kit from the midline [24]. A third step is a gain of repulsion to Slits

Newcomers for midline found in transcription and translation

As mentioned before, in the past few years, there has been little new receptors and ligands added to the list of molecules acting on midline crossing. By contrast, there is a recent burst of findings that reveals that known molecules and biochemical pathways can modulate the activity and expression of axon guidance receptors in commissural axons.

Three reports show that transcription plays a central role in axon guidance at the midline by controlling the expression level of several receptors.

In

Conclusion

Although there still is a pile of questions to answer, there has been some constant progress toward a better understanding of midline crossing in vertebrates. An emerging picture is that in every part of the CNS, commissural axons are guided by the same basic set of molecules: netrin1/DCC, a morphogen (Wnt5a or Shh), Slits and Robos, some secreted semaphorins, one Neuropilin, and PlexinA. This suggests that the signalling pathways and cross talk are highly conserved between commissural axons.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

I thank Athena Ypsilanti and Valérie Castellani for critical reading of the manuscript. This work is supported by the Agence Nationale pour la Recherche (ANR), and the Fondation pour la Recherche Médicale (Equipes labelisées FRM).

References (53)

  • P.T. Yam et al.

    Sonic hedgehog guides axons through a noncanonical. Src-family-kinase-dependent signaling pathway

    Neuron

    (2009)
  • R. Shirasaki et al.

    Change in chemoattractant responsiveness of developing axons at an intermediate target

    Science

    (1998)
  • Y. Sasaki et al.

    Fyn and Cdk5 mediate semaphorin-3A signaling, which is involved in regulation of dendrite orientation in cerebral cortex

    Neuron

    (2002)
  • L. Yang et al.

    A frazzled/DCC-dependent transcriptional switch regulates midline axon guidance

    Science

    (2009)
  • J. Tcherkezian et al.

    Transmembrane receptor DCC associates with protein synthesis machinery and regulates translation

    Cell

    (2010)
  • B. Spitzweck et al.

    Distinct protein domains and expression patterns confer divergent axon guidance functions for Drosophila Robo receptors

    Cell

    (2010)
  • N. Renier et al.

    Genetic dissection of the function of hindbrain axonal commissures

    PLoS Biol

    (2010)
  • R. Sperry

    Some effects of disconnecting the cerebral hemispheres

    Science

    (1982)
  • L.K. Paul et al.

    Agenesis of the corpus callosum: genetic, developmental and functional aspects of connectivity

    Nat Rev Neurosci

    (2007)
  • B.J. Molyneaux et al.

    Novel subtype-specific genes identify distinct subpopulations of callosal projection neurons

    J Neurosci

    (2009)
  • T. Shu et al.

    Slit2 guides both precrossing and postcrossing callosal axons at the midline in vivo

    J Neurosci

    (2003)
  • W. Andrews et al.

    Robo1 regulates the development of major axon tracts and interneuron migration in the forebrain

    Development

    (2006)
  • T.R. Keeble et al.

    The Wnt receptor Ryk is required for Wnt5a-mediated axon guidance on the contralateral side of the corpus callosum

    J Neurosci

    (2006)
  • G. Lopez-Bendito et al.

    Robo1 and Robo2 cooperate to control the guidance of major axonal tracts in the mammalian forebrain

    J Neurosci

    (2007)
  • S.M. Islam et al.

    Draxin, a repulsive guidance protein for spinal cord and forebrain commissures

    Science

    (2009)
  • M.A. Tischfield et al.

    Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance

    Cell

    (2010)
  • Cited by (0)

    View full text