Cloning and Functional Characterization of DSCAML1, a Novel DSCAM-like Cell Adhesion Molecule That Mediates Homophilic Intercellular Adhesion

Agarwala, Kishan Lal; Ganesh, Subramaniam; Tsutsumi, Yukie; Suzuki, Toshimitsu; Amano, Kenji; Yamakawa, Kazuhiro

doi:10.1006/bbrc.2001.5214

Cited by 62 publications

(50 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2b and data not shown). Thus, as shown previously 7,8,10 , Dscams and Sidekicks mediate homophilic adhesion. To assess heterophilic adhesion, we labelled transfected populations separately with red and green fluorescent dyes.…”

supporting

confidence: 84%

Dscam and Sidekick proteins direct lamina-specific synaptic connections in vertebrate retina

Yamagata

Sanes

2008

Nature

349

370

View full text Add to dashboard Cite

Synaptic circuits in the retina transform visual input gathered by photoreceptors into messages that retinal ganglion cells (RGCs) send to the brain. Processes of retinal interneurons (amacrine and bipolar cells) form synapses on dendrites of RGCs in the inner plexiform layer (IPL). The IPL is divided into at least 10 parallel sublaminae; subsets of interneurons and RGCs arborize and form synapses in just one or a few of them [1][2][3] . These lamina-specific circuits determine the visual features to which RGC subtypes respond [3][4][5] . Here we show that four closely related immunoglobulin superfamily (IgSF) adhesion molecules-Dscam (Down's syndrome cell adhesion molecule), DscamL (refs 6-9), Sidekick-1 and Sidekick-2 (ref. 10)-are expressed in chick by non-overlapping subsets of interneurons and RGCs that form synapses in distinct IPL sublaminae. Moreover, each protein is concentrated within the appropriate sublaminae and each mediates homophilic adhesion. Loss-and gain-of-function studies in vivo indicate that these IgSF members participate in determining the IPL sublaminae in which synaptic partners arborize and connect. Thus, vertebrate Dscams, like Drosophila Dscams 11-19 , play roles in neural connectivity. Together, our results on Dscams and Sidekicks suggest the existence of an IgSF code for laminar specificity in retina and, by implication, in other parts of the central nervous system.We previously showed that Sidekick-1 and Sidekick-2, large transmembrane adhesion molecules of the IgSF, are expressed by complementary subsets of amacrine, bipolar and ganglion cells in chick retina 10 . Double-label in situ hybridization revealed that only 10-15% of RGCs were positive for each Sidekick (Supplementary Table 1). We speculated that Sidekick-negative retinal neurons might express genes encoding related molecules. Homology searches of genomic databases revealed that their closest relatives are the Dscams 6-9 , which, like Sidekicks, contain multiple immunoglobulin and fibronectin type III domains, plus a carboxy terminus predicted to bind PDZ domains (Fig. 1a and Supplementary Fig. 1). Moreover, vertebrate Dscams are related to Drosophila Dscams, which have been implicated in neural specificity [11][12][13][14][15][16][17][18][19] , although they lack the complex pattern of alternative splicing found in Drosophila Dscam-1. We therefore cloned chick Dscam and DscamL, the orthologues of mammalian Dscam and Dscam-like-1, respectively, and assessed their expression in retina. Dscam and DscamL, like Sidekicks, were expressed by non-overlapping subsets of retinal neurons between embryonic day (E) 12 and hatching (E21) (Fig. 1b and Supplementary Fig. 2). None of the Dscam-positive neurons expressed either Sidekick (Fig. 1c and Supplementary Fig. 3). Thus, Dscams and Sidekicks mark four distinct sets of presynaptic (amacrine and bipolar) and postsynaptic cells (RGCs) that arborize in the IPL.To localize Dscam and Sidekick proteins, we generated antibodies specific for each ( Supplementary Fig. 4) and used them to i...

show abstract

supporting

confidence: 84%

Dscam and Sidekick proteins direct lamina-specific synaptic connections in vertebrate retina

Yamagata

Sanes

2008

Nature

349

370

View full text Add to dashboard Cite

show abstract

“…Mouse DSCAM functions in a highly analogous way, promoting self-avoidance for both arborization (isoneuronal) and the prevention of fasciculation (heteroneuronal). Although the vertebrate genes are not extensively alternatively spliced, they do undergo homophilic and paralogue-specific binding 5,27,28 . The coexistence of Dscam-expressing amacrine cell populations suggests that stratification in different IPL layers may allow reuse of DSCAM as a recognition signal.…”

mentioning

confidence: 99%

“…Alternatively, additional co-signals may distinguish distinct cell populations, consistent with the continued lack of interaction between bNOS and dopaminergic cells in the Dscam 2/2 retina. Additional complexity for self-recognition could also be introduced by other Dscam gene family members, such as Dscam-like 1 (Dscaml1), which is expressed in a similar but discrete population of retinal neurons 27,28 (P.G.F. and R.W.B., unpublished) or the highly homologous Sidekick proteins 29 .…”

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 nematode genomes currently available do not contain Dscam (ø). Data adapted from Yamakawa et al 1998;Schmucker et al 2000;Agarwala 2001;Graveley et al 2004;Watson et al 2005;Crayton et al 2006;Fusaoka et al 2006;Brites et al 2008;and D. Schmucker, unpubl. ''docking site'' (66 nucleotides in Drosophila melanogaster) is located downstream from the constant exon 5 and upstream of the variable exon 6 cluster. Shorter sequences termed ''selector sequences'' that are conspicuously complementary to sequences of the docking site are located upstream of each of the alternative exon 6 variants (Graveley 2005).…”

Section: Mechanisms and Molecular Control Of Dscam's Alternative Splimentioning

confidence: 99%

“…Since then, the DSCAM gene has been duplicated at least once in vertebrates and insects (Crayton et al 2006;Brites et al 2008). The second human DSCAM gene, DSCAML1, is located on chromosome band 11q23, a locus associated with Gilles de la Tourette and Jacobsen syndromes (Agarwala 2001). However, the most intriguing changes in gene structure have occurred in arthropods where several duplications of exons generated three large tandem arrays that are alternatively spliced (Schmucker et al 2000).…”

mentioning

confidence: 99%

Dscam and DSCAM: complex genes in simple animals, complex animals yet simple genes

Schmucker¹,

Chen²

2009

Genes Dev.

157

138

View full text Add to dashboard Cite

Cadherins and the immunoglobulin (Ig) proteins give rise to a multitude of surface receptors, which function as diverse cell adhesion molecules (CAMs) or signaltransducing receptors. These functions are often interdependent, and rely on a high degree of specificity in homophilic binding as well as heterophilic interactions. The Drosophila receptor Dscam is an exceptional example of homophilic binding specificity involved in a number of important biological processes, such as neural wiring and innate immunity. Combinatorial use of alternatively spliced Ig-domains enables the generation of an estimated 18,000 isoform-specific homophilic receptor pairs. Although isoform diversity of Dscam is unique to arthropods, recent genetic analysis of vertebrate DSCAM (Down Syndrome Cell Adhesion Molecule) genes has revealed an intriguing conservation of molecular functions underlying neural wiring. This review covers the multiple functions of Dscam across different species highlighting its remarkable versatility as well as its conserved basic functions in neural development. We discuss how an unprecedented expansion of complex alternative splicing has been uniquely employed by arthropods to generate diverse surface receptors, important for cell-cell communication, molecular self-recognition in neurons, and innate immune defenses. We end with a speculative hypothesis reconciling the striking differences in Dscam and DSCAM gene structures with their conserved functions in molecular recognition underlying neural circuit formation.

show abstract

Cloning and Functional Characterization of DSCAML1, a Novel DSCAM-like Cell Adhesion Molecule That Mediates Homophilic Intercellular Adhesion

Cited by 62 publications

References 49 publications

Dscam and Sidekick proteins direct lamina-specific synaptic connections in vertebrate retina

Dscam and Sidekick proteins direct lamina-specific synaptic connections in vertebrate retina

Neurite arborization and mosaic spacing in the mouse retina require DSCAM

Dscam and DSCAM: complex genes in simple animals, complex animals yet simple genes

Contact Info

Product

Resources

About