Slit1 and Slit2 Cooperate to Prevent Premature Midline Crossing of Retinal Axons in the Mouse Visual System

Plump, Andrew S.; Erskine, Lynda; Sabatier, Christelle; Brose, Katja; Epstein, Charles J.; Goodman, Corey S.; Mason, Carol A.; Tessier‐Lavigne, Marc

doi:10.1016/s0896-6273(01)00586-4

Cited by 407 publications

(406 citation statements)

References 49 publications

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“…For example, mice with Robo mutations have defects in midline crossing of spinal cord commissural axons (Long et al, 2004). Other axon populations dependent on Slit/Robo signaling include major forebrain tracts and commissures (Andrews et al, 2006;Bagri et al, 2002), retinal axons (Plump et al, 2002;Thompson et al, 2006), and motor axons (Hammond et al, 2005), as well as others.…”

Section: Resultsmentioning

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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Section: Resultsmentioning

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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“…Various ensembles of immature radial glia, other noncanonical glia and transient neurons predominate at these sites Lindwall et al 2007) (See Chédotal and Richards 2010). Glial cells at midline loci express both inhibitory and growth-promoting guidance factors, and serve to cordon axons into their proper tracts and to prevent them from straying (e.g., Plump et al 2002). Other molecules on midline glia are repulsive and induce some growth cones to turn away from the midline.…”

Section: Substrata In Vivomentioning

confidence: 99%

Cellular Strategies of Axonal Pathfinding

Raper

Mason

2010

Cold Spring Harbor Perspectives in Biology

157

130

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Axons follow highly stereotyped and reproducible trajectories to their targets. In this review we address the properties of the first pioneer neurons to grow in the developing nervous system and what has been learned over the past several decades about the extracellular and cell surface substrata on which axons grow. We then discuss the types of guidance cues and their receptors that influence axon extension, what determines where cues are expressed, and how axons respond to the cues they encounter in their environment.T his article provides an overview of how growth cones respond to the cellular substrata and molecular cues they encounter as they extend through the developing nervous system. It elaborates on the primer by Kolodkin and TessierLavigne (2010) and touches on many of the topics covered in greater detail in the articles that follow. The first sections describe how axons extend in a directed manner, the substrata on which they grow, interactions between pioneer and follower axons, and growth cone behaviors in emerging tracts and at decision points. The subsequent sections discuss examples of specific cues, their distributions, how their distributions are determined, and how growth cones integrate multiple cues during pathfinding. AXONS EXTEND IN VIVO IN A DIRECTED MANNERThe first person to visualize the growing tips of axons, Ramon y Cajal, recognized that axons for the most part grow very efficiently towards their ultimate targets. He was a strong advocate for axons finding their way in response to chemotactic cues:"If one admits that neuroblasts are endowed with chemotactic properties, then one might also imagine that they are capable of ameboid movements, initiated by factors secreted from epithelial, neural, or mesodermal elements. As a result, their processes may be oriented in the direction of chemical gradients, and thus guided to the secreting cells" (Ramon y Cajal 1892; trans. English, 1995).This surprisingly modern outlook emphasizing directed guidance was temporarily derailed by the views of Weiss during the 1920s and 1930s. He first argued that functional specificity did not arise as a consequence of specific axonal connections (Weiss 1936), and later argued that nonspecific mechanical guidance cues play a predominant role in guiding axons and organizing them into nerves and tracts

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“…117 However, the expression of Robo proteins by endothelial cells in normal or metastatic tissue has not been reported yet and slit1/slit2 knockouts have an apparent normal vasculature. 122 Therefore, the physiological relevance of these results is still unclear. Slits might also have other function in metastatic cells.…”

Section: The Slits and Robosmentioning

confidence: 99%

The brain within the tumor: new roles for axon guidance molecules in cancers

2005

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Slits, semaphorins and netrins are three families of proteins that can attract or repel growing axons and migrating neurons in the developing nervous system of vertebrates and invertebrates. Recent studies have shown that they are widely expressed outside the nervous system and that they may play important roles in cancers. Several of the genes encoding these proteins are localized on chromosomal region associated with frequent loss-of-heterozygosity in tumors and cancer cell lines and there is also significant hypermethylation of their promoter suggesting that they may act as tumor suppressors. In addition, proteins in all these families and their receptors appear to control the vascularization of the tumors. Last, many axon guidance molecules also regulate cell migration and apoptosis in normal and tumorigenic tissues. Overall, this suggests that molecules that could mimick or block the activity of axon guidance molecules may be used as therapeutic agents for the treatment of malignancy.

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Slit1 and Slit2 Cooperate to Prevent Premature Midline Crossing of Retinal Axons in the Mouse Visual System

Cited by 407 publications

References 49 publications

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

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

Cellular Strategies of Axonal Pathfinding

The brain within the tumor: new roles for axon guidance molecules in cancers

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