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      Hox Paralog Group 2 Genes Control the Migration of Mouse Pontine Neurons through Slit-Robo Signaling

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          The pontine neurons (PN) represent a major source of mossy fiber projections to the cerebellum. During mouse hindbrain development, PN migrate tangentially and sequentially along both the anteroposterior (AP) and dorsoventral (DV) axes. Unlike DV migration, which is controlled by the Netrin-1/Dcc attractive pathway, little is known about the molecular mechanisms guiding PN migration along the AP axis. Here, we show that Hoxa2 and Hoxb2 are required both intrinsically and extrinsically to maintain normal AP migration of subsets of PN, by preventing their premature ventral attraction towards the midline. Moreover, the migration defects observed in Hoxa2 and Hoxb2 mutant mice were phenocopied in compound Robo1;Robo2, Slit1;Slit2, and Robo2;Slit2 knockout animals, indicating that these guidance molecules act downstream of Hox genes to control PN migration. Indeed, using chromatin immunoprecipitation assays, we further demonstrated that Robo2 is a direct target of Hoxa2 in vivo and that maintenance of high Robo and Slit expression levels was impaired in Hoxa2 mutant mice. Lastly, the analysis of Phox2b-deficient mice indicated that the facial motor nucleus is a major Slit signaling source required to prevent premature ventral migration of PN. These findings provide novel insights into the molecular control of neuronal migration from transcription factor to regulation of guidance receptor and ligand expression. Specifically, they address the question of how exposure to multiple guidance cues along the AP and DV axes is regulated at the transcriptional level and in turn translated into stereotyped migratory responses during tangential migration of neurons in the developing mammalian brain.

          Author Summary

          In the developing central nervous system, neurons migrate sometimes over long distances from their birthplace to their final location, where they condense in specific nuclei. The precise positioning of migrating neurons is critical to the building of ordered connectivity with their target partners. Little is known about how exposure of migrating neurons to simultaneous attractive and repulsive guidance cues may be integrated at the transcriptional level and in turn translated into directional migratory responses specific for each neuronal population. Here, we focus on the molecular mechanisms regulating the directionality of long-distance migration of pontine neurons in the mouse brainstem. Such neurons belong to the so-called precerebellar system, which is essential for coordinated motor activity, and provide the principal input to the cerebellum. We provide evidence for the implication of homeodomain transcription factors of the Hox gene family in the control of pontine neuron migration along the brain rostrocaudal axis. We identify the guidance receptor Robo2 as a direct target gene of the Hoxa2 gene. We further show that repulsive signaling mediated through the Robo2 receptor expressed in migrating neurons and its ligand Slit2 secreted from the facial motor nucleus are key components of the molecular guidance system that maintains caudorostral migration and prevents premature attraction towards the brainstem ventral midline. Our data provide a conceptual framework to understand how transcriptional regulation of the response to environmental guidance cues controls stereotyped neuronal migratory behavior in the developing mammalian brain.


          Homeodomain-containing Hox factors are well-known for controlling body patterning, but a new study reveals a novel role for these genes in controlling the long-distance tangential migration of neurons in the mouse brain stem through transcriptional regulation of Robo receptor-Slit ligand family guidance molecules.

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          Most cited references 83

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            Modification of gene activity in mouse embryos in utero by a tamoxifen-inducible form of Cre recombinase.

            The ability to generate specific genetic modifications in mice provides a powerful approach to assess gene function. When genetic modifications have been generated in the germ line, however, the resulting phenotype often only reflects the first time a gene has an influence on - or is necessary for - a particular biological process. Therefore, systems allowing conditional genetic modification have been developed (for a review, see [1]); for example, inducible forms of the Cre recombinase from P1 phage have been generated that can catalyse intramolecular recombination between target recognition sequences (loxP sites) in response to ligand [2] [3] [4] [5]. Here, we assessed whether a tamoxifen-inducible form of Cre recombinase (Cre-ERTM) could be used to modify gene activity in the mouse embryo in utero. Using the enhancer of the Wnt1 gene to restrict the expression of Cre-ERTM to the embryonic neural tube, we found that a single injection of tamoxifen into pregnant mice induced Cre-mediated recombination within the embryonic central nervous system, thereby activating expression of a reporter gene. Induction was ligand dependent, rapid and efficient. The results demonstrate that tamoxifen-inducible recombination can be used to effectively modify gene function in the mouse embryo.
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              Modulating Hox gene functions during animal body patterning.

              With their power to shape animal morphology, few genes have captured the imagination of biologists as the evolutionarily conserved members of the Hox clusters have done. Recent research has provided new insight into how Hox proteins cause morphological diversity at the organismal and evolutionary levels. Furthermore, an expanding collection of sequences that are directly regulated by Hox proteins provides information on the specificity of target-gene activation, which might allow the successful prediction of novel Hox-response genes. Finally, the recent discovery of microRNA genes within the Hox gene clusters indicates yet another level of control by Hox genes in development and evolution.

                Author and article information

                Role: Academic Editor
                PLoS Biol
                PLoS Biology
                Public Library of Science (San Francisco, USA )
                June 2008
                10 June 2008
                : 6
                : 6
                [1 ] Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, UMR 7104, CU de Strasbourg, Illkirch, France
                [2 ] CNRS UMR 7102 Université Pierre et Marie Curie–Paris 6, Paris, France
                [3 ] Friedrich Miescher Institute, Basel, Switzerland
                [4 ] CNRS UMR8542, Ecole Normale Supérieure, Paris, France
                Baylor College of Medicine, United States of America
                Author notes
                * To whom correspondence should be addressed. E-mail: Filippo.Rijli@
                07-PLBI-RA-4189R2 plbi-06-06-09
                Copyright: © 2008 Geisen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Page count
                Pages: 17
                Research Article
                Developmental Biology
                Custom metadata
                Geisen MJ, Di Meglio T, Pasqualetti M, Ducret S, Brunet J-F, et al. (2008) Hox paralog group 2 genes control the migration of mouse pontine neurons through Slit-Robo signaling. PLoS Biol 6(6): e142. doi: 10.1371/journal.pbio.0060142

                Life sciences


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