Molecular Mechanisms Controlling Midline Crossing by Precerebellar Neurons

Meglio, Thomas Di; Nguyen-Ba-Charvet, Kim T.; Tessier‐Lavigne, Marc; Sotelo, Constantino; Chédotal, Alain

doi:10.1523/jneurosci.0078-08.2008

Cited by 59 publications

(66 citation statements)

References 57 publications

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“…A similar result has been reported for axons of precerebellar neurons of the inferior olive. These axons normally cross the hindbrain floor plate, are prevented from crossing in the Robo3 mutant, and are not rescued in Robo1/2/3 mutants (Di Meglio et al, 2008). Hence, there must be additional mechanisms by which Robo3 allows midline crossing.…”

Section: Existence Of Another Slit Receptormentioning

confidence: 99%

Collaborative and Specialized Functions of Robo1 and Robo2 in Spinal Commissural Axon Guidance

Jaworski¹,

Long²,

Tessier‐Lavigne³

2010

Journal of Neuroscience

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142

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Commissural neurons project axons across the floor plate at the spinal cord ventral midline. After crossing, commissural axons turn rostrally, sort into distinct positions within the ventrolateral funiculus, and never reenter the floor plate. Robo1 and Robo2 are receptors for the midline repellents Slit1-Slit3, and upregulation of Robos in post-crossing axons allows expulsion from the floor plate and prevents recrossing. Before crossing, Robo-mediated repulsion is attenuated by the divergent family member Robo3/Rig-1. To define the relative contributions of Robo family members to commissural axon guidance in mice, we studied commissural axon trajectories in combination mutants between Robo1, Robo2, and Robo3. Our results suggest the existence of another receptor contributing to Slit repulsion because the failure of midline crossing in Robo3 mutants is rescued largely but not entirely by loss of both Robo1 and Robo2 and because axon guidance defects in mice lacking both Robo1 and Robo2 are less severe than in mice lacking all Slits. Analysis of post-crossing axon trajectories indicates that Robo1 and Robo2 collaborate to prevent axons from reentering the gray matter and projecting dorsally alongside contralateral pre-crossing axons. We also discovered a previously unappreciated division of labor between Robo1 and Robo2 in post-crossing axons. Robo2 is required for axons to project away from the floor plate into the lateral funiculus. In contrast, Robo1 prevents axonal stalling after crossing. Our results reveal specialized and complementary actions of Robo1 and Robo2 in commissural axon guidance and suggest the existence of an as yet unidentified Slit receptor.

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Section: Existence Of Another Slit Receptormentioning

confidence: 99%

Collaborative and Specialized Functions of Robo1 and Robo2 in Spinal Commissural Axon Guidance

Jaworski¹,

Long²,

Tessier‐Lavigne³

2010

Journal of Neuroscience

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142

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“…The mossy-fibre-projecting precerebellar neurons (PCN) migrate marginally beneath the pial surface of the hindbrain, forming two streams: the anteroventrally directed anterior extramural stream (AES); and the ventrally directed posterior extramural stream (PES). Although the ventral directions of the AES/PES have been attributed to the Netrin and SLIT/ROBO families (Serafini et al, 1996;Yee et al, 1999;Alcantara et al, 2000;Taniguchi et al, 2002;Marillat et al, 2004;Di Meglio et al, 2008), the mechanisms that control the marginal positioning of AES/PES cells, as well as the anterior direction of the AES, are poorly understood.…”

Section: Introductionmentioning

confidence: 99%

SDF1/CXCR4 signalling regulates two distinct processes of precerebellar neuronal migration and its depletion leads to abnormal pontine nuclei formation

et al. 2009

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The development of mossy-fibre projecting precerebellar neurons (PCN) presents a classical example of tangential neuronal migration. PCN migrate tangentially along marginal streams beneath the pial surface from the lower rhombic lip to specific locations in the hindbrain, where they form precerebellar nuclei. Among them, the pontine neurons follow a stereotypic anteroventral-directed pathway to form the pontine nuclei in the pons. The guidance mechanisms that determine the marginal migration of PCN and the anterior migration of pontine neurons are poorly understood. Here, we report that a chemokine SDF1 (also known as CXCL12) derived from the meningeal tissue regulates the migratory pathways of PCN. PCN are chemoattracted by the meningeal tissue, an effect that is mimicked by an SDF1 source. Analysis of knockout mice for the Sdf1 receptor Cxcr4 shows that both the marginal migration of PCN and the anterior migration of pontine neurons are disrupted. We provide further evidence that SDF1/CXCR4 signalling regulates these two processes cell-autonomously. As a result of disrupted neuronal migration, pontine nuclei formation was highly abnormal, with the presence of multiple ectopic pontine clusters posteriorly. The ectopic pontine clusters led to ectopic collateral branch formation from the corticospinal tract. Our results together demonstrate crucial roles for SDF1/CXCR4 in multiple aspects of PCN migration and highlight the deleterious consequence of derailed migration on proper nuclei formation. Furthermore, we provide the first in vivo evidence that pontine neurons themselves induce collateral branching from the corticospinal axons.

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“…SLIT2 encodes a ligand of the ROBO family of axonal guidance receptors of which the dyslexia candidate ROBO1 is a member. 86,126 In the study by Igo et al, 26 linkage with 'single word reading efficiency' was reported for marker ATA5A09 on 13q12.3 (Table 1). ATA5A09 is located within the HMGB1 gene (http://www.ensembl.org/homo_ sapiens).…”

mentioning

confidence: 95%

“…86,126 As shown and described in more detail in (the legend of) Figure 2, the rate and direction of outgrowth is critically dependent on the exact receptor composition in the plasma membrane. As they have fibronectin type III domains very similar to those of the DCC receptor protein (http://www.…”

mentioning

confidence: 96%

“…86 When only a ROBO1 receptor is present in the neuronal plasma membrane (3), binding of SLIT (2) to one of the Ig domains of the ROBO1 receptor 86 eventually leads-through the inhibition of CDC42-to stimulation of neurite outgrowth but repulsion away from the SLIT guidance cues. 86,126,133,134 As indicated in Figure 2, the activation of the ROBO1 and DCC receptors leads to signaling via CDC42 131 and cytoplasmic ERK1 and ERK2 proteins 132 resulting in changes in the cytoskeletal organization of microtubules and actin filaments and (eventually) in neurite outgrowth. 86,126,133,134 Two other dyslexia candidates, S100B and HMGB1, can also result in CDC42 135 and ERK1/2 132 activation and neurite outgrowth by binding to RAGE 106,127 ( Figure 1b).…”

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confidence: 99%

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A theoretical molecular network for dyslexia: integrating available genetic findings

et al. 2010

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Developmental dyslexia is a common specific childhood learning disorder with a strong heritable component. Previous studies using different genetic approaches have identified several genetic loci and candidate genes for dyslexia. In this article, we have integrated the current knowledge on 14 dyslexia candidate genes suggested by cytogenetic findings, linkage and association studies. We found that 10 of the 14 dyslexia candidate genes (ROBO1, KIAA0319, KIAA0319L, S100B, DOCK4, FMR1, DIP2A, GTF2I, DYX1C1 and DCDC2) fit into a theoretical molecular network involved in neuronal migration and neurite outgrowth. Based on this, we also propose three novel dyslexia candidate genes (SLIT2, HMGB1 and VAPA) from known linkage regions, and we discuss the possible involvement of genes emerging from the two reported genome-wide association studies for reading impairment-related phenotypes in the identified network.

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Molecular Mechanisms Controlling Midline Crossing by Precerebellar Neurons

Cited by 59 publications

References 57 publications

Collaborative and Specialized Functions of Robo1 and Robo2 in Spinal Commissural Axon Guidance

Collaborative and Specialized Functions of Robo1 and Robo2 in Spinal Commissural Axon Guidance

SDF1/CXCR4 signalling regulates two distinct processes of precerebellar neuronal migration and its depletion leads to abnormal pontine nuclei formation

A theoretical molecular network for dyslexia: integrating available genetic findings

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