The Journal of Neuroscience, June 18, 2008, 28(25):6285-6294; doi:10.1523/JNEUROSCI.0078-08.2008
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Development/Plasticity/Repair
Molecular Mechanisms Controlling Midline Crossing by Precerebellar Neurons
Thomas Di Meglio,1,2
Kim T. Nguyen-Ba-Charvet,1,2
Marc Tessier-Lavigne,3
Constantino Sotelo,1,2,4 and
Alain Chédotal1,2
1Centre National de la Recherche Scientifique, Unité Mixte de Recherche (UMR) 7102, 2Université Pierre et Marie Curie, UMR 7102, F-75005 Paris, France, 3Genentech, South San Francisco, California 94080, and 4Cátedra de Neurobiología del Desarrollo "Remedios Caro Almela," Instituto de Neurociencias de Alicante, Universidad Miguel Hernández de Elche–Consejo Superior de Investigaciones Científicas, 03550 San Juan de Alicante, Alicante, Spain
Correspondence should be addressed to Dr. Alain Chédotal, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche en Santé 592, Institut de la Vision, F-75012 Paris, France. Email: alain.chedotal{at}inserm.fr
Precerebellar neurons of the inferior olive (IO) and lateral reticular nucleus (LRN) migrate tangentially from the rhombic lip toward the floor plate following parallel pathways. This process is thought to involve netrin-1 attraction. However, whereas the cell bodies of LRN neurons cross the midline, IO neurons are unable to do so. In many systems and species, axon guidance and cell migration at the midline are controlled by Slits and their receptor Robos. We showed previously that precerebellar axons and neurons do not cross the midline in the absence of the Robo3 receptor. To determine whether this signaling by Slits and the two other Robo receptors, Robo1 and Robo2, also regulates precerebellar neuron behavior at the floor plate, we studied the phenotype of Slit1/2 and Robo1/2/3 compound mutants. Our results showed that many IO neurons can cross the midline in absence of Slit1/2 or Robo1/2, supporting a role for midline repellents in guiding precerebellar neurons. We also show that these molecules control the development of the lamellation of the inferior olivary complex. Last, the analysis of Robo1/2/3 triple mutants suggests that Robo3 inhibits Robo1/2 repulsion in precrossing LRN axons but not in IO axons in which it has a dominant and distinct function.
Key words: cerebellum; inferior olive; floor plate; Roundabout; Slit; migration
Received Jan. 8, 2008;
revised April 18, 2008;
accepted May 7, 2008.
Correspondence should be addressed to Dr. Alain Chédotal, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche en Santé 592, Institut de la Vision, F-75012 Paris, France. Email: alain.chedotal{at}inserm.fr
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