Analysis of Dscam Diversity in Regulating Axon Guidance in Drosophila Mushroom Bodies

Zhan, Xiao Li; Clemens, James C.; Neves, Guilherme; Hattori, Daisuke; Flanagan, John J.; Hummel, Thomas; Vasconcelos, Maria Luísa; Chess, Andrew; Zipursky, S. Lawrence

doi:10.1016/j.neuron.2004.07.020

Cited by 212 publications

(326 citation statements)

References 60 publications

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“…Is this process highly regulated or does it occur in a random or stochastic manner? Microarray experiments have revealed little if any regulation of exon 6 splicing 11,27 , which is consistent with the biology of Dscam. In the nervous system, it seems that the actual identity of the Dscam isoforms that are expressed is unimportant, provided that each neuron expresses a different set of isoforms than the neighboring neurons 11,[28][29][30][31] .…”

supporting

confidence: 63%

“…Microarray experiments have revealed little if any regulation of exon 6 splicing 11,27 , which is consistent with the biology of Dscam. In the nervous system, it seems that the actual identity of the Dscam isoforms that are expressed is unimportant, provided that each neuron expresses a different set of isoforms than the neighboring neurons 11,[28][29][30][31] . Similarly, within the immune system, where Dscam functions in a manner analogous to vertebrate antibodies 13,16 , hemocytes must be capable of expressing most if not all of the potential Dscam isoforms to mount an effective immune defense against invading pathogens.…”

supporting

confidence: 63%

“…For example, in the nervous system, Dscam is required for the proper wiring of Bolwigs nerve 5 , olfactory receptor neurons 7 , projection neurons of the olfactory system 8 , mushroom body neurons [9][10][11] and mechanosensory neurons 12 . In every case that has been examined, mutations in Dscam result in neural wiring defects.…”

mentioning

confidence: 99%

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A regulator of Dscam mutually exclusive splicing fidelity

Olson

Blanchette

Park

et al. 2007

Nat Struct Mol Biol

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The Down syndrome cell adhesion molecule (Dscam) gene has essential roles in neural wiring and pathogen recognition in Drosophila melanogaster. Dscam encodes 38,016 distinct isoforms via extensive alternative splicing. The 95 alternative exons in Dscam are organized into clusters that are spliced in a mutually exclusive manner. The exon 6 cluster contains 48 variable exons and uses a complex system of competing RNA structures to ensure that only one variable exon is included. Here we show that the heterogeneous nuclear ribonucleoprotein hrp36 acts specifically within, and throughout, the exon 6 cluster to prevent the inclusion of multiple exons. Moreover, hrp36 prevents serine/arginine-rich proteins from promoting the ectopic inclusion of multiple exon 6 variants. Thus, the fidelity of mutually exclusive splicing in the exon 6 cluster is governed by an intricate combination of alternative RNA structures and a globally acting splicing repressor.Pre-mRNA splicing is frequently used to regulate important biological processes. It is currently estimated that between 60% and 75% of human genes encode alternatively spliced pre-mRNAs 1,2 . Though most of these genes encode 2-3 different isoforms, there are several examples of genes that can generate much larger repertoires of mRNAs. For example, the human KCNMA1 gene can generate ~500 different isoforms, and the three NRXN genes together produce over 2,000 isoforms 3,4 . However, by far the most notable example is the D. melanogaster Dscam gene, which can generate 38,016 isoforms 5 .Correspondence should be addressed to B.R.G. (graveley@neuron.uchc.edu). (Fig. 1a). These variable exons are organized in clusters; the exon 4, 6, 9 and 17 clusters contain 12, 48, 33 and 2 variable exons, respectively. Importantly, the exons within each cluster are spliced in a mutually exclusive manner-only one exon from each cluster is included in the mRNA. The exon 4, 6 and 9 clusters encode alternative versions of extracellular immunoglobulin repeats, whereas the exon 17 cluster encodes two different transmembrane domains, such that each of the 38,016 isoforms has the same overall domain structure.From a mechanistic view one of the most puzzling aspects of Dscam is how the splicing of the large clusters of exons occurs in a mutually exclusive manner. Thousands of eukaryotic genes contain regions that have two mutually exclusive exons, and a variety of mechanisms are known that ensure that only one exon is included in these mRNAs. These mechanisms involve steric hindrance, the use of both the major and minor spliceosomes, and the nonsense-mediated decay pathway 15 . However, none of these mechanisms explain how the variable clusters in Dscam can be spliced in a mutually exclusive manner.Insight into the mechanism by which Dscam splicing occurs in a mutually exclusive manner was obtained from comparative genomics 16,17 . The exon 6 cluster contains two classes of conserved elements: the docking site, which is located in the intron downstream of constitutive exon 5, and the sele...

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supporting

confidence: 63%

supporting

confidence: 63%

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A regulator of Dscam mutually exclusive splicing fidelity

Olson

Blanchette

Park

et al. 2007

Nat Struct Mol Biol

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“…And finally, Dscam1 is required for the segregation of sister branches in mushroom body neurons, a process similar to self-avoidance [8]. These observations led to the proposal that Dscam1 promotes homophilic repulsion in vivo [9] [7]. Note that in previous publications we referred to this Dscam paralog as Dscam.…”

Section: Reviewmentioning

confidence: 83%

“…Expression studies in mushroom body neurons (as well as several other subclasses) argue that many isoforms are expressed in each neuron and that the expression pattern is largely random [6]. In addition, genetic studies demonstrated that the type of isoform expressed in each MB neuron is not important; rather, what is crucial is that an individual MB neuron expresses different isoforms from its neighbors [9][10][11].…”

Section: Reviewmentioning

confidence: 99%

Dscam-mediated repulsion controls tiling and self-avoidance

Millard

Zipursky

2008

Current Opinion in Neurobiology

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SummaryRecent studies have uncovered the molecular basis of self-avoidance and tiling, two fundamental principles required for the formation of neural circuits. Both of these wiring strategies are established through homophilic repulsion between Dscam proteins expressed on opposing cell surfaces. In Drosophila, Dscam1 mediates self-avoidance whereas Dscam2 mediates tiling. In contrast, phenotypes in the retina of the DSCAM mutant mouse indicate that DSCAM functions in both selfavoidance and tiling. These findings suggest that homophilic recognition molecules that have classically been defined as adhesive, may also function as repulsive cues, and that Dscam proteins specialize in this function.

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The Drosophila ortholog of the Zc3h14 RNA binding protein acts within neurons to pattern axon projection in the developing brain

Kelly

Bienkowski

Banerjee

et al. 2015

Developmental Neurobiology

105

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The dNab2 polyadenosine RNA binding protein is the D. melanogaster ortholog of the vertebrate ZC3H14 protein, which is lost in a form of inherited intellectual disability (ID). Human ZC3H14 can rescue D. melanogaster dNab2 mutant phenotypes when expressed in all neurons of the developing nervous system, suggesting that dNab2/ZC3H14 performs well-conserved roles in neurons. However, the cellular and molecular requirements for dNab2/ZC3H14 in the developing nervous system have not been defined in any organism. Here we show that dNab2 is autonomously required within neurons to pattern axon projection from Kenyon neurons into the mushroom bodies, which are required for associative olfactory learning and memory in insects. Mushroom body axons lacking dNab2 project aberrantly across the brain midline and also show evidence of defective branching. Coupled with the prior finding that ZC3H14 is highly expressed in rodent hippocampal neurons, this requirement for dNab2 in mushroom body neurons suggests that dNab2/ZC3H14 has a conserved role in supporting axon projection and branching. Consistent with this idea, loss of dNab2 impairs short-term memory in a courtship conditioning assay. Taken together these results reveal a cell-autonomous requirement for the dNab2 RNA binding protein in mushroom body development and provide a window into potential neurodevelopmental functions of the human ZC3H14 protein.

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Analysis of Dscam Diversity in Regulating Axon Guidance in Drosophila Mushroom Bodies

Cited by 212 publications

References 60 publications

A regulator of Dscam mutually exclusive splicing fidelity

A regulator of Dscam mutually exclusive splicing fidelity

Dscam-mediated repulsion controls tiling and self-avoidance

The Drosophila ortholog of the Zc3h14 RNA binding protein acts within neurons to pattern axon projection in the developing brain

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