Further tales of the midline
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).
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