Mutations in a Human
            <i>ROBO</i>
            Gene Disrupt Hindbrain Axon Pathway Crossing and Morphogenesis

Jen, Joanna C.; Chan, Wai Man; Bosley, Thomas M.; Wan, Jijun; Carr, Janai R.; Rüb, Udo; Shattuck, David W.; Salamon, G; Kudo, Lili C.; Jiang, Ou; Lin, Doris; Salih, Mustafa A.; Kansu, Tülay; Dhalaan, Hesham Al; Zayed, Zayed Al; MacDonald, David B.; Stigsby, B.; Plaitakis, Andreas; Dretakis, Emm. K.; Gottlob, Irène; Pieh, Christina; Traboulsi, Elias I.; Wang, Qing Kenneth; Wang, Lejin; Andrews, Caroline; Yamada, Koki; Demer, Joseph L.; Karim, Salmaan; Alger, Jeffry R.; Geschwind, Daniel H.; Deller, Thomas; Sicotte, Nancy L.; Nelson, Stanley F.; Baloh, Robert W.; Engle, Elizabeth C.

doi:10.1126/science.1096437

Cited by 354 publications

(320 citation statements)

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“…Marillat et al (2004) have demonstrated a role for Rig1/Robo3 in controlling midline crossing of hindbrain precerebellar neurons and axons. Human patients with horizontal gaze palsy with progressive scoliosis (HGPPS) were reported to have mutations in Rig1/ Robo3, and functional studies have shown defects in commissural hindbrain projections and pontine nuclei (Jen et al, 2004). Gilthorpe et al (2002) have shown that early and late stage chick cerebellar rhombic lip fragments are repelled by Slit2.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of medulloblastoma cell invasion by Slit

et al. 2006

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Section: Discussionmentioning

confidence: 99%

Inhibition of medulloblastoma cell invasion by Slit

et al. 2006

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“…These isoforms of Robo3 have different affinities to Slit2 (Camurri et al, 2005). In humans, a point mutation in the Robo3 isoform A signal peptide results in horizontal gaze palsy with progressive scoliosis (HGPPS), even though the Robo3 isoform B remains intact (Jen et al, 2004). This raises an interesting point for future determination of Slit binding characteristics of Robo1 and Dutt1.…”

mentioning

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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“…The first roundabout gene, Robo, was identified in Drosophila in a screen for genes regulating midline crossing in the CNS (Seeger et al, 1993). Three Robo genes have been found in Drosophila (Kidd et al, 1998;Rajagopalan et al, 2000a;Simpson et al, 2000b) and mammals Li et al, 1999;Yuan et al, 1999;Jen et al, 2004), and one in Caenorhabditis elegans (Zallen et al, 1998). Mammalian Slits can bind to all Robo receptors with comparable affinity Li et al, 1999;Sabatier et al, 2004).…”

Section: Introductionmentioning

confidence: 99%