The Molecular Diversity of Dscam Is Functionally Required for Neuronal Wiring Specificity in Drosophila

Chen, Brian E.; Kondo, Masahiro; Garnier, Amélie; Watson, Fiona; Püettmann-Holgado, Roland; Lamar, David R.; Schmucker, Dietmar

doi:10.1016/j.cell.2006.03.034

Cited by 192 publications

(190 citation statements)

References 39 publications

Supporting

Mentioning

189

Contrasting

Order By: Relevance

“…Examples of functional diversity among AS-produced proteins include developmental switches that control sex determination in Drosophila (reviewed by Lopez, 1998), membrane pumps that have different directionality of net transport (Lazaridis et al, 2000), and the 38 016 variants of the single Drosophila Dscam gene, which encode a set of immunoglobulin superfamily receptors that function in axon guidance and immune responses (Watson et al, 2005;Chen et al, 2006a). This is a perfunctory list, and knowledge of how AS affects healthy and pathological cellular phenotypes grows almost daily (for recent reviews see Lipscombe, 2005;Stamm et al, 2005;Stetefeld and Ruegg, 2005).…”

Section: Alternative Splicing As a Mechanism For Generating Phenotypimentioning

confidence: 99%

Quantitative and evolutionary biology of alternative splicing: how changing the mix of alternative transcripts affects phenotypic plasticity and reaction norms

Marden

2006

Heredity

View full text Add to dashboard Cite

Alternative splicing (AS) of pre-messenger RNA is a common phenomenon that creates different transcripts from a single gene, and these alternative transcripts affect phenotypes. The majority of AS research has examined tissue and developmental specificity of expression of particular AS transcripts, how this specificity affects cell function, and how aberrant AS is related to disease. Few studies have examined quantitative between-individual variation in AS within a cell or tissue type, or in relation to phenotypes, but the results are compelling: quantitative variation in AS affects plastic traits such as stress, anxiety, fear, egg production, muscle performance, energetics and plant growth. Genomic analyses of AS are also at a nascent stage, but have revealed a number of significant evolutionary patterns. Growing knowledge of upstream genes and kinases that regulate AS provides the as-yet little explored potential to examine how these genes and pathways respond to environmental and genotype variables. Research in this area can provide glimpses of a labyrinth of genetic architectures that have rarely been considered in evolutionary and organismal biology, or in quantitative genetics. The scarcity of contribution to knowledge about AS from these fields is illustrated by the fact that heritability of quantitative variation in AS has not yet been determined for any gene in any organism. New research tactics that incorporate quantitative analyses of AS will allow organismal and evolutionary biologists to attain a fuller mechanistic understanding of many of the traits they study, and may lead to more rapid discovery of functionally important polymorphisms.

show abstract

Section: Alternative Splicing As a Mechanism For Generating Phenotypimentioning

confidence: 99%

Quantitative and evolutionary biology of alternative splicing: how changing the mix of alternative transcripts affects phenotypic plasticity and reaction norms

Marden

2006

Heredity

View full text Add to dashboard Cite

show abstract

“…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%

A regulator of Dscam mutually exclusive splicing fidelity

Olson

Blanchette

Park

et al. 2007

Nat Struct Mol Biol

View full text Add to dashboard Cite

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...

show abstract

“…Therefore, Drosophila neurons use DSCAM for isoneuronal self-avoidance and arborization because each cell recognizes only its own processes, which express the same set of isoforms 8,9,24 . Reducing or eliminating the diversity of DSCAM isoforms perturbs Drosophila circuit organization 25,26 . Dscam2 in Drosophila is not extensively alternatively spliced and mediates heteroneuronal cell avoidance in tiling In wild-type retinas double-labelled for two Dscam-expressing cell populations (dopaminergic amacrine and bNOS-positive), the cell bodies and processes appear independent.…”

mentioning

confidence: 99%

Neurite arborization and mosaic spacing in the mouse retina require DSCAM

Fuerst

Koizumi

Burgess

2008

Nature

275

345

View full text Add to dashboard Cite

To establish functional circuitry, retinal neurons occupy spatial domains by arborizing their processes, which requires the selfavoidance of neurites from an individual cell, and by spacing their cell bodies, which requires positioning the soma and establishing a zone within which other cells of the same type are excluded 1 . The mosaic patterns of distinct cell types form independently and overlap. The cues that direct these processes in the vertebrate retina are not known 2,3 . Here we show that some types of retinal amacrine cells from mice with a spontaneous mutation in Down syndrome cell adhesion molecule (Dscam), a gene encoding an immunoglobulin-superfamily member adhesion molecule 4,5 , have defects in the arborization of processes and in the spacing of cell bodies. In the mutant retina, cells that would normally express Dscam have hyperfasciculated processes, preventing them from creating an orderly arbor. Also, their cell bodies are randomly distributed or pulled into clumps rather than being regularly spaced mosaics. Our results indicate that mouse DSCAM mediates isoneuronal self-avoidance for arborization and heteroneuronal self-avoidance within specific cell types to prevent fasciculation and to preserve mosaic spacing. These functions are analogous to those of Drosophila DSCAM (ref. 6) and DSCAM2 (ref. 7). DSCAM may function similarly in other regions of the mammalian nervous system, and this role may extend to other members of the mammalian Dscam gene family.We have identified a spontaneous mutation in mice that creates a loss-of-function allele of Dscam, the Drosophila homologues of which function in both isoneuronal self-avoidance for dendrite arborization and heteroneuronal self-avoidance for axon tiling [7][8][9][10][11][12] . The recessive mutation arose in the BALB/cByJ genetic background and caused an overt neurological phenotype. Mutant and wild-type mice are indistinguishable at birth, but are severely uncoordinated by postnatal day 3 (P3); as adults, the mutant mice have spontaneous seizures and kyphosis, but are fertile and long-lived (.24 months; see http://www.jax.org/research/media/wild_type.html for video). Through positional cloning (see Methods), a mutation was identified in Dscam. Sequencing of genomic and complementary DNA from affected mice revealed a 38-bp deletion in exon 17, causing a frame shift resulting in ten unique amino acids followed by a premature stop codon (Supplementary Fig. 1). This mutation truncates the protein in the second fibronectin repeat (Fig. 1a). Dscam messenger RNA levels in the brain were reduced by 70% in affected mice, consistent with nonsense-mediated decay (Fig. 1b).

show abstract

The Molecular Diversity of Dscam Is Functionally Required for Neuronal Wiring Specificity in Drosophila

Cited by 192 publications

References 39 publications

Quantitative and evolutionary biology of alternative splicing: how changing the mix of alternative transcripts affects phenotypic plasticity and reaction norms

Quantitative and evolutionary biology of alternative splicing: how changing the mix of alternative transcripts affects phenotypic plasticity and reaction norms

A regulator of Dscam mutually exclusive splicing fidelity

Neurite arborization and mosaic spacing in the mouse retina require DSCAM

Contact Info

Product

Resources

About