Crucial roles of Robo proteins in midline crossing of cerebellofugal axons and lack of their up-regulation after midline crossing

Tamada, Atsushi; Kumada, Tatsuro; Zhu, Yan; Matsumoto, Tomoko; Hatanaka, Yasuo; Muguruma, Keiko; Chen, Zhe; Tanabe, Yukito; Torigoe, Makio; Yamauchi, Kenta; Ōyama, Hiroshi; Nishida, Keiya; Murakami, Fujio

doi:10.1186/1749-8104-3-29

Cited by 53 publications

(66 citation statements)

References 27 publications

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“…The primary antibodies used were as follows: a rabbit polyclonal anti-nrp2 antibody (1:250), a rabbit polyclonal anti-TH antibody (1:250; Millipore Bioscience Research Reagents), a sheep polyclonal anti-TH antibody (1:100; Millipore Bioscience Research Reagents), a rat monoclonal anti-dopamine transporter (DAT; Slc6a3; Mouse Genome Informatics) antibody (1:1000; Millipore Bioscience Research Reagents), and a rabbit polyclonal anti-␤-gal antibody (1:5000; ICN Biomedicals). The procedures for the anti-nrp2 antibody production followed those of anti-Robo antibodies (Tamada et al, 2008). The specificity of the anti-nrp2 antibody was confirmed by immunostaining with antibodies preabsorbed with a nrp2 ectodomain-Fc fusion protein or Fc protein and examination of immunoreactivities in nrp2-knock-out mice preparations.…”

Section: Methodsmentioning

confidence: 99%

FGF8 Signaling Regulates Growth of Midbrain Dopaminergic Axons by Inducing Semaphorin 3F

Yamauchi¹,

Mizushima²,

Tamada³

et al. 2009

J. Neurosci.

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Accumulating evidence indicates that signaling centers controlling the dorsoventral (DV) polarization of the neural tube, the roof plate and the floor plate, play crucial roles in axon guidance along the DV axis. However, the role of signaling centers regulating the rostrocaudal (RC) polarization of the neural tube in axon guidance along the RC axis remains unknown. Here, we show that a signaling center located at the midbrain-hindbrain boundary (MHB) regulates the rostrally directed growth of axons from midbrain dopaminergic neurons (mDANs). We found that beads soaked with fibroblast growth factor 8 (FGF8), a signaling molecule that mediates patterning activities of the MHB, repelled mDAN axons that extended through the diencephalon. This repulsion may be mediated by semaphorin 3F (sema3F) because (1) FGF8-soaked beads induced an increase in expression of sema3F, (2) sema3F expression in the midbrain was essentially abolished by the application of an FGF receptor tyrosine kinase inhibitor, and (3) mDAN axonal growth was also inhibited by sema3F. Furthermore, mDAN axons expressed a sema3F receptor, neuropilin-2 (nrp2), and the removal of nrp-2 by gene targeting caused caudal growth of mDAN axons. These results indicate that the MHB signaling center regulates the growth polarity of mDAN axons along the RC axis by inducing sema3F.

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Section: Methodsmentioning

confidence: 99%

FGF8 Signaling Regulates Growth of Midbrain Dopaminergic Axons by Inducing Semaphorin 3F

Yamauchi¹,

Mizushima²,

Tamada³

et al. 2009

J. Neurosci.

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“…Within the Atoh1 transcriptional cascade, both commissural and ipsilateral neurons postmitotically express two closely related LIM-HD transcription factors, Lhx2 and Lhx9 (Wilson et al, 2008). Interestingly, the analysis of the Lhx2 and Lhx9 double-knockout mice has indicated that these factors regulate the expression of Robo3 (Wilson et al, 2008), which is an essential regulator for midline crossing (Marillat et al, 2004;Sabatier et al, 2004;Tamada et al, 2008) by selectively silencing the repellent action of Slit-Robo1 signaling . Although this gene-targeting study suggests that these LIM-HD factors are required for midline crossing by commissural axons, it is currently obscure whether the expression of these factors is sufficient to specify axonal projection laterality.…”

Section: Research Articlementioning

confidence: 99%

“…Here, we further characterized the expression of cell surface molecules that may be involved in the guidance of midbrain commissural axons. We first examined Robo3 expression using whole-mount immunohistochemistry on flat-mounted midbrain preparations, as Robo3 has been shown to be a crucial regulator for midline crossing by commissural axons in the spinal cord and the hindbrain (Marillat et al, 2004;Sabatier et al, 2004;Tamada et al, 2008). We found that Robo3 was selectively expressed on axons growing toward the floor plate, as judged by expression analysis of the pan-neuronal marker Tuj1 and Robo3 ( Fig.…”

Section: Molecular Characterization Of Midbrain Commissural Neuronsmentioning

confidence: 99%

Dbx1 triggers crucial molecular programs required for midline crossing by midbrain commissural axons

Inamata

Shirasaki

2014

Development

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Axon guidance by commissural neurons has been well documented, providing us with a molecular logic of how midline crossing is achieved during development. Despite these advances, knowledge of the intrinsic genetic programs is still limited and it remains obscure whether the expression of a single transcription factor is sufficient to activate transcriptional programs that ultimately enable midline crossing. Here, we show in the mouse that the homeodomain transcription factor Dbx1 is expressed by a subset of progenitor cells that give rise to commissural neurons in the dorsal midbrain. Gainand loss-of-function analyses indicate that the expression of Dbx1 alone is sufficient and necessary to trigger midline crossing in vivo. We also show that Robo3 controls midline crossing as a crucial downstream effector of the Dbx1-activated molecular programs. Furthermore, Dbx1 suppresses the expression of the transcriptional program for ipsilateral neuron differentiation in parallel. These results suggest that a single transcription factor, Dbx1, has an essential function in assigning midline-crossing identity, thereby contributing crucially to the establishment of the wiring laterality in the developing nervous system.

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“…In the developing spinal cord and hindbrain, Robo3 is expressed at high levels on commissural axons until they have crossed the floor plate (Marillat et al, 2004;Sabatier et al, 2004;Tamada et al, 2008). In Robo3 knockout mice, most commissural axons fail to cross the midline and neuronal migration across the floor plate is prevented (Marillat et al, 2004;Sabatier et al, 2004;Tamada et al, 2008) (see Fig.…”

Section: Development 1944mentioning

confidence: 99%

“…In Robo3 knockout mice, most commissural axons fail to cross the midline and neuronal migration across the floor plate is prevented (Marillat et al, 2004;Sabatier et al, 2004;Tamada et al, 2008) (see Fig. 2C).…”

Section: Regulation Of Cell Adhesionmentioning

confidence: 99%

Moving away from the midline: new developments for Slit and Robo

2010

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SummaryIn most tissues, the precise control of cell migration and cellcell interaction is of paramount importance to the development of a functional structure. Several families of secreted molecules have been implicated in regulating these aspects of development, including the Slits and their Robo receptors. These proteins have well described roles in axon guidance but by influencing cell polarity and adhesion, they participate in many developmental processes in diverse cell types. We review recent progress in understanding both the molecular mechanisms that modulate Slit/Robo expression and their functions in neural and non-neural tissue. Key words: Axon guidance, Cell migration, Cell-cell interaction IntroductionIn most organisms, the central nervous system (CNS) develops along a bilateral axis of symmetry located at the midline (Placzek and Briscoe, 2005). During development, the ventral midline or floor plate acts as an organiser through the secretion of diffusible proteins (Placzek and Briscoe, 2005;Gore et al., 2008), which control the growth of axons and dendrites and the migration of neurons across the midline. In the forebrain, glial or neuronal cells delineate the midline (see Glossary, Box 1) and also control axon guidance. For more than two decades, many developmental neurobiologists have tried to understand the mechanisms that control midline crossing in the CNS and to answer some key questions. Firstly, how are commissural axons (see Glossary, Box 1) attracted to the midline and how do their growth cones (see Glossary, Box1) receive and integrate the multiple and contrasting signals released by midline cells? Secondly, what are the molecular and signalling changes that enable commissural axons to leave the midline and often to switch to a longitudinal growth mode? All midline-derived axon guidance factors are expressed at other locations in many developing and mature tissues, where they control a wide range of biological processes.Roundabout receptors (Robo) and their Slit ligands form one of the most crucial ligand-receptor pairings among the axon guidance molecules. Robos were identified in Drosophila in a mutant screen for genes that control the midline crossing of commissural axons (Kidd et al., 1998;Seeger et al., 1993). Similarly, Slit was discovered in Drosophila as a protein secreted by midline glia (Rothberg et al., 1988;Rothberg et al., 1990). Homologues of both proteins have since been discovered in many species (for a review, see . However, the Slit/Robo couple not only functions in axon guidance but also in a variety of developmental Development 137, 1939Development 137, -1952Development 137, (2010 Commissural axons Axons with cell bodies (somata) located on one side of the central nervous system (CNS) that project axons across the midline to contact target cells on the opposite side. Growth cone A specialised bulbous enlargement at the end of growing axons that is characterised by dynamic filamentous extensions, known as filopodia. They sense the environment and respond to adhesi...

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Crucial roles of Robo proteins in midline crossing of cerebellofugal axons and lack of their up-regulation after midline crossing

Cited by 53 publications

References 27 publications

FGF8 Signaling Regulates Growth of Midbrain Dopaminergic Axons by Inducing Semaphorin 3F

FGF8 Signaling Regulates Growth of Midbrain Dopaminergic Axons by Inducing Semaphorin 3F

Dbx1 triggers crucial molecular programs required for midline crossing by midbrain commissural axons

Moving away from the midline: new developments for Slit and Robo

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