DSCAM
Ensembl | |||||||||
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| UniProt | |||||||||
| RefSeq (mRNA) | |||||||||
| RefSeq (protein) | |||||||||
| Location (UCSC) | Chr 21: 40.01 – 40.85 Mb | Chr 16: 96.59 – 97.17 Mb | |||||||
| PubMed search | [3] | [4] | |||||||
| View/Edit Human | View/Edit Mouse |
| Down syndrome cell adhesion molecule, chordates | |
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| Identifiers | |
| Symbol | DSCAM_chordates |
| InterPro | IPR033027 |
DSCAM and Dscam are both abbreviations for Down syndrome cell adhesion molecule.[5] In humans, DSCAM refers to a gene that encodes one of several protein isoforms.[6]
A homologue of the Dscam protein in Drosophila melanogaster has 38,016 isoforms[7] arising from four variable exon clusters (12, 48, 33 and 2 alternatives, respectively).[5] By comparison, the entire Drosophila melanogaster genome only has 15,016 genes. The diversity of isoforms from alternative splicing of the Dscam1 gene in D. melanogaster allows every neuron in the fly to display a unique set of Dscam proteins on its cell surface. Dscam interaction stimulates neuronal self-avoidance mechanisms that are essential for normal neural circuit development.[8]
History/discovery
The DSCAM protein structure is conserved, with roughly more than 20% amino acid identity across the
DSCAM was first identified in an effort to characterize proteins located within
Gene
The DSCAM gene has been identified in the DS critical region. Dscam is predicted to be a transmembrane protein and a member of the immunoglobulin (Ig) superfamily of cell adhesion molecules. It is expressed in the developing nervous system with the highest level of expression occurring in the fetal brain. When this gene is over-expressed in the developing fetal central nervous system, it leads to Down syndrome. Diverse glycoproteins of cell surfaces and extracellular matrices, operationally termed as 'adhesion molecules' are important in the specification of cell interactions during development as well as maintenance and regeneration of the nervous system.[13]
Another DSCAM-like gene,
Some intriguing changes in the
Comparing the
| Species | Gene | mRNA | Protein |
|---|---|---|---|
| H. sapiens | DSCAM | NM_001389.3 | NP_001380.2 |
| P. troglodytes | DSCAM | XM_001171538.1 | XP_001171538.1 |
| M. mulatta | DSCAM | XM_002803124.1 | XP_002803170.1 |
| C. lupus | DSCAM | XM_544893.3 | XP_544893.3 |
| B. taurus | DSCAM | XM_002685111.2 | XP_002685157.1 |
| M. musculus | Dscam | NM_031174.4 | NP_112451.1 |
| R. norvegicus | Dscam | NM_133587.1 | NP_598271.1 |
| G. gallus | DSCAM | XM_416734.3 | XP_416734.3 |
| D. rerio | dscam | NM_001030224.1 | NP_001025395.1 |
| D. melanogaster | CG42330 | NM_001043131.2 | NP_001036596.2 |
| A. gambiae | AgaP_AGAP007092 | XM_308666.4 | XP_308666.4 |
Functions
Like many neuronal receptors, Dscam proteins have multiple functions, with repulsive and attractive roles that are dependent on the type of ligand that they interact with.
Immunity
Invertebrates do not have antibody-based immune systems. Instead, invertebrates rely on their innate immune system to eliminate infectious entities. The task of detecting and responding to a diverse pool of infectious agents are accomplished by
Dscam is found to have a role in phagocytosis in insects. The splicing pattern of the gene accompanying the phagocytic activity is specific to the type of infectious pathogen. In mosquitoes, the silencing of the Anopheles gambiae Dscam (AgDscam) disables its capacity to fight Plasmodium. The specificity of the Dscam recognition mechanism allows the mosquitoes of this species to differentiate the infection between bacteria and Plasmodium, and between Plasmodium berghei and Plasmodium falciparum.[19][25]
Regulation of synaptogenesis
Self-avoidance is a mechanism where the
DSCAM is recognized to be involved in this process in both vertebrates and invertebrates during neural development. Cell aggregation assays show that cell adhesion molecules, such as DSCAM, belonging to the
Dscam1, of drosophila, may be one of the molecules involved in counteracting the
In addition to homophilic repulsion, Dscam1 mediates repulsion between
Furthermore, DSCAM is thought to have a role in 'tiling' during the drosophila's neuronal development. Tiling is a mechanism in which the processes from cells that share the same function work to create nerve bundles in a defined territory to create a pattern of non-overlapping dendritic or axonal fields.[32] Dscam1 and Dscam2 appear to be involved in axonal branching and tiling in Drosophila.[33][34] Tiling occurs when homophilic repulsion mediated by Dscam2 prevents the processes of the same class of cells from overlapping.[8] While both Dscam1 and Dscam2 mediate homophilic repulsion, the Dscam2 gene (unlike Dscam1) only encodes two alternative isoforms and thus lacks possible molecular diversity.[31] Consequently, the role of Dscam2, in either self-avoidance or cell-type-specific avoidance, occurs depending on which isoform or ratio of isoforms that the neuron expresses.[31]
Interactions
Many Ig superfamily molecules bind homophilically and heterophilically, and Dscam/DSCAM proteins are no exception. Vertebrate DSCAMs and DSCAML1s have not only been shown to bind homophilically (i.e., DSCAM–DSCAM or DSCAML1–DSCAML1, and not DSCAM–DSCAML1),[35][36] but also have cell-type specific, mutually exclusive, expression patterns.[36][37] Due to the combinatorial use of alternative exons, the homophilic binding specificity of Drosophila Dscam is amplified to tens of thousands of potential homodimers.,[38][39] Biochemical assays (cell-to-cell and bead-to-cell binding assays) were used to demonstrate that isoform-specific homodimerization occurs with remarkable binding specificity. This reveals that Dscam diversity can give rise to >18,000 distinct homodimers.[12]
Clinical significance
The role of Ig-CAMs in human development and disease is only beginning to be elucidated. This may be of particular interest with respect to the DSCAMs, as DSCAM maps to chromosome 21 in a region critical for the neurocognitive and other defects of Down syndrome
A study of
See also
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000171587 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000050272 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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Additional sources
- Li W, Guan KL (July 2004). "The Down syndrome cell adhesion molecule (DSCAM) interacts with and activates Pak". J. Biol. Chem. 279 (31): 32824–31. PMID 15169762.
- Wojtowicz WM, Flanagan JJ, Millard SS, Zipursky SL, Clemens JC (September 2004). "Alternative splicing of Drosophila Dscam generates axon guidance receptors that exhibit isoform-specific homophilic binding". Cell. 118 (5): 619–33. PMID 15339666.
- Watson FL, Püttmann-Holgado R, Thomas F, et al. (September 2005). "Extensive diversity of Ig-superfamily proteins in the immune system of insects". Science. 309 (5742): 1874–8. S2CID 10039688.
- Chen BE, Kondo M, Garnier A, et al. (May 2006). "The molecular diversity of Dscam is functionally required for neuronal wiring specificity in Drosophila". Cell. 125 (3): 607–20. PMID 16678102.