Rig-1 a new member of Robo family genes exhibits distinct pattern of expression during mouse development

The mechanisms controlling axon guidance are of fundamental importance in understanding brain development. Growing corticospinal and somatosensory axons cross the midline in the medulla to reach their targets and thus form the basis of contralateral motor control and sensory input. The motor and sensory projections appeared uncrossed in patients with horizontal gaze palsy with progressive scoliosis (HGPPS). In patients affected with HGPPS, we identified mutations in the ROBO3 gene, which shares homology with roundabout genes important in axon guidance in developing Drosophila , zebrafish, and mouse. Like its murine homolog Rig1/Robo3, but unlike other Robo proteins, ROBO3 is required for hindbrain axon midline crossing.

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“…3E). This observation is consistent with the hindbrain-specific expression of the homologous gene in mouse (21,26).…”

supporting

confidence: 89%

Mutations in a Human ROBO Gene Disrupt Hindbrain Axon Pathway Crossing and Morphogenesis

Jen

Chan

Bosley

et al. 2004

Science

354

304

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“…Whole mount in situ hybridization for Robo1 was performed on embryonic day (E)12.5 intact mouse embryos using a modified protocol (Wilkinson, 1992;Henrique et al, 1995) as described by Camurri et al (Camurri et al, 2004). To assess protein expression in the Robo1 knockouts, gel-electrophoresis and immunoblotting were performed as previously described (Hivert et al, 2002).…”

Section: Generation and Characterization Of Robo1 Knockout Micementioning

confidence: 99%

Robo1 regulates the development of major axon tracts and interneuron migration in the forebrain

et al. 2006

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The Slit genes encode secreted ligands that regulate axon branching, commissural axon pathfinding and neuronal migration. The principal identified receptor for Slit is Robo (Roundabout in Drosophila). To investigate Slit signalling in forebrain development, we generated Robo1 knockout mice by targeted deletion of exon 5 of the Robo1 gene. Homozygote knockout mice died at birth, but prenatally displayed major defects in axon pathfinding and cortical interneuron migration. Axon pathfinding defects included dysgenesis of the corpus callosum and hippocampal commissure, and abnormalities in corticothalamic and thalamocortical targeting. Slit2 and Slit1/2 double mutants display malformations in callosal development, and in corticothalamic and thalamocortical targeting, as well as optic tract defects. In these animals, corticothalamic axons form large fasciculated bundles that aberrantly cross the midline at the level of the hippocampal and anterior commissures, and more caudally at the medial preoptic area. Such phenotypes of corticothalamic targeting were not observed in Robo1 knockout mice but, instead, both corticothalamic and thalamocortical axons aberrantly arrived at their respective targets at least 1 day earlier than controls. By contrast, in Slit mutants, fewer thalamic axons actually arrive in the cortex during development. Finally, significantly more interneurons (up to twice as many at E12.5 and E15.5) migrated into the cortex of Robo1 knockout mice, particularly in both rostral and parietal regions, but not caudal cortex. These results indicate that Robo1 mutants have distinct phenotypes, some of which are different from those described in Slit mutants, suggesting that additional ligands, receptors or receptor partners are likely to be involved in Slit/Robo signalling.

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“…For example, alternative splicing of Robo2 and 3 transcripts results in isoforms with distinct affinity for Slit binding and/or differences in intracellular signaling (Camurri et al, 2004;Yue et al, 2006). Tissue-specific alternative mRNA splicing appears to contribute to the spatial complexity of Robo2 and 3 expression (Challa et al, 2005;Dalkic et al, 2006).…”

Section: Nih Public Accessmentioning

confidence: 99%

The Slit receptor Robo1 is predominantly expressed via the Dutt1 alternative promoter in pioneer neurons in the embryonic mouse brain and spinal cord

Nural

Farmer

Mastick

2007

Gene Expression Patterns

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Robo1 is a member of the Roundabout (Robo) family of receptors for the Slit axon guidance cues. In mice (and humans), the Robo1 locus has alternative promoters producing two transcript isoforms, Robo1 and Dutt1. These isoforms have unique 5′ termini, predicted to encode distinct N-terminal amino acids, but share the rest of their 3′ exons. To determine the spatial expression of the Robo1 and Dutt1 isoforms, we generated isoform-specific RNA probes, and carried out in situ hybridization on E10.5 mouse embryos, the stage in early neuron differentiation when many major axon pathways are established. The two isoforms had distinct expression patterns that partially overlapped. Dutt1 was the predominant isoform, with widespread expression in regions of post-mitotic neurons and neuroepithelial cells. The Robo1 isoform had a distinct expression pattern restricted to subsets of neurons, many of which were Dutt1-negative. Dutt1 was the main isoform expressed in spinal cord commissural neurons. For both probes, the main hybridization signal was limited to two spots in the nuclei of individual cells. This study shows distinct expression patterns for the Dutt1 and Robo1 alternative promoters in the embryonic nervous system. Keywords axon guidance; neuron; Robo; Slit; longitudinal axon; commissural axon; dorsal root ganglion Results and DiscussionGrowth cones navigate by selectively responding to molecular cues in their environment. Different types of axons differ in their responses to cues, depending on their expression of specific combinations of guidance receptors. In contrast to the great diversity in neuron types and their axon projection patterns, a surprisingly small number of axon guidance receptors have been identified to date. However, single receptor genes could potentially give rise to multiple receptor isoforms through mechanisms such as alternative promoters and differential mRNA splicing.The Slit repellents and their Robo receptors are a major guidance system conserved from invertebrates to vertebrates (Dickson and Gilestro, 2006). The Roundabout (Robo) family of Corresponding author: Grant Mastick, Department of Biology, University of Nevada, Reno NV 89557, Phone: 775-784-6168, FAX: 775-784-1650, gmastick@unr.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. transmembrane receptors was first identified in Drosophila in a mutant screen for genes that control midline crossing by pioneer axons (Seeger et al., 1993). Slit/Robo signaling has a primary function in keeping axons out of the Slit+ midline, both in commissural axons to prevent re-crossing, as well as ...

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Rig-1 a new member of Robo family genes exhibits distinct pattern of expression during mouse development

Cited by 25 publications

References 15 publications

Mutations in a Human ROBO Gene Disrupt Hindbrain Axon Pathway Crossing and Morphogenesis

Mutations in a Human ROBO Gene Disrupt Hindbrain Axon Pathway Crossing and Morphogenesis

Robo1 regulates the development of major axon tracts and interneuron migration in the forebrain

The Slit receptor Robo1 is predominantly expressed via the Dutt1 alternative promoter in pioneer neurons in the embryonic mouse brain and spinal cord

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