View source for DSCAM

{{Short description|Protein-coding gene in the species Homo sapiens}}
{{Use dmy dates|date=April 2016}}
{{Infobox gene}}
{{Infobox protein family
|Name=Down syndrome cell adhesion molecule, [[chordate]]s
|Symbol=DSCAM_chordates
|InterPro=IPR033027
}}

'''DSCAM''' and '''''Dscam''''' are both abbreviations for '''Down syndrome cell adhesion molecule'''.<ref name=Schmucker>{{cite journal |vauthors=Schmucker D, Clemens JC, Shu H, Worby CA, Xiao J, Muda M, Dixon JE, Zipursky SL |title=Drosophila Dscam is an axon guidance receptor exhibiting extraordinary molecular diversity |journal=Cell |volume=101 |issue=6 |pages=671–84 |date=June 2000 |pmid=10892653 |doi= 10.1016/S0092-8674(00)80878-8|doi-access=free }}</ref> In humans, DSCAM refers to a [[gene]] that encodes one of several [[protein|protein isoforms]].<ref>{{cite journal|last=Alves-Sampaio|first=Alexandra|author2=José Antonio Troca-Marín |author3=María Luz Montesinos |title=NMDA-Mediated Regulation of DSCAM Dendritic Local Translation Is Lost in a Mouse Model of Down's Syndrome|journal=The Journal of Neuroscience|volume=30|issue=40|pages=13537–13548|date=6 October 2010|doi=10.1523/JNEUROSCI.3457-10.2010|pmid=20926679|pmc=6634725|doi-access=free}}</ref>

[[Down syndrome]] (DS), caused by [[trisomy 21]], is the most common birth defect associated with [[intellectual disability]]. DSCAM plays a crucial role in the development of DS: it is expressed in the developing nervous system, with the highest level of expression occurring in the fetal brain. When over-expressed in the developing fetal central nervous system, it leads to Down syndrome.

A homologue of the ''Dscam'' protein in ''[[Drosophila melanogaster]]'' has 38,016 [[Alternative splicing|isoforms]]<ref>{{cite journal|last=Neves|first=G.|author2=Zucker J |author3=Daly M |author4=Chess A. |title=Stochastic yet biased expression of multiple Dscam splice variants by individual cells.|journal=Nature Genetics|date=February 2004|volume=36|pages=240–246|pmid=14758360|doi=10.1038/ng1299|issue=3|doi-access=free}}</ref> arising from four variable [[exon]] clusters (12, 48, 33 and 2 alternatives, respectively).<ref name="Schmucker"/> By comparison, the entire ''[[Drosophila melanogaster]]'' genome only has 15,016 genes.  The diversity of isoforms from alternative splicing of the Dscam1 gene in [[Drosophila melanogaster|''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.<ref name=Hattori>{{cite journal |vauthors=Hattori D, Millard SS, Wojtowicz WM, Zipursky SL |title=Dscam-mediated cell recognition regulates neural circuit formation |journal=Annu. Rev. Cell Dev. Biol. |volume=24 |issue= 1|pages=597–620 |year=2008 |pmid=18837673 |doi=10.1146/annurev.cellbio.24.110707.175250 |pmc=2711549}}</ref>

==History/discovery==
The DSCAM protein structure is conserved, with roughly more than 20% amino acid identity across the [[deuterostome]]s and [[protostome]]s, and assuming an ancestral homologous gene, places the origin of the DSCAM gene at >600&nbsp;million years ago. Since then, the DSCAM gene has been duplicated at least once in [[vertebrates]] and insects.<ref name="CraytonPowell2006">{{cite journal|last1=Crayton|first1=MackE|last2=Powell|first2=BradfordC|last3=Vision|first3=ToddJ|last4=Giddings|first4=MorganC|journal=BMC Evolutionary Biology|title=Tracking the evolution of alternatively spliced exons within the Dscam family|volume=6|issue=1|year=2006|pages=16|issn=1471-2148|doi=10.1186/1471-2148-6-16|pmid=16483367|pmc=1397879 |bibcode=2006BMCEE...6...16C |doi-access=free }} {{open access}}</ref><ref name="BritesMcTaggart2008">{{cite journal|last1=Brites|first1=D.|last2=McTaggart|first2=S.|last3=Morris|first3=K.|last4=Anderson|first4=J.|last5=Thomas|first5=K.|last6=Colson|first6=I.|last7=Fabbro|first7=T.|last8=Little|first8=T. J.|last9=Ebert|first9=D.|last10=Du Pasquier|first10=L.|title=The Dscam Homologue of the Crustacean Daphnia Is Diversified by Alternative Splicing Like in Insects|journal=Molecular Biology and Evolution|volume=25|issue=7|year=2008|pages=1429–1439|issn=0737-4038|doi=10.1093/molbev/msn087|pmid=18403399|doi-access=free}}</ref>

DSCAM was first identified in an effort to characterize proteins located within [[Research of Down syndrome-related genes|human chromosome band 21q22]], a region known to play a critical role in Down syndrome.<ref name="Yamakawa1998">{{cite journal|last1=Yamakawa|first1=K|title=DSCAM: a novel member of the immunoglobulin superfamily maps in a Down syndrome region and is involved in the development of the nervous system|journal=Human Molecular Genetics|volume=7|issue=2|year=1998|pages=227–237|issn=1460-2083|doi=10.1093/hmg/7.2.227|pmid=9426258|doi-access=free}}</ref> The name Down syndrome cell adhesion molecule was chosen for a combination of reasons including: 1) chromosomal location, 2) its appropriate (normal) expression in developing neural tissue, and 3) its structure as an Ig [[Receptor (biochemistry)|receptor]] related to other [[cell adhesion molecule]]s (CAMs).<ref name="SchmuckerChen2009">{{cite journal|last1=Schmucker|first1=D.|last2=Chen|first2=B.|title=Dscam and DSCAM: complex genes in simple animals, complex animals yet simple genes|journal=Genes & Development|volume=23|issue=2|year=2009|pages=147–156|issn=0890-9369|doi=10.1101/gad.1752909|pmid=19171779|doi-access=free}}</ref>

==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 superfamily|immunoglobulin (Ig) superfamily]] of [[cell adhesion molecule]]s. 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 [[glycoprotein]]s 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.<ref name="pmid10925149">{{cite journal|year=2000|title=Down syndrome cell adhesion molecule DSCAM mediates homophilic intercellular adhesion.|journal=Brain Res Mol Brain Res|volume=79|issue=1–2|pages=118–26|doi=10.1016/s0169-328x(00)00108-x|pmid=10925149|vauthors=Agarwala KL, Nakamura S, Tsutsumi Y, Yamakawa K}}</ref>

Another DSCAM-like gene, [[DSCAML1]], is located on chromosome band 11q23, a [[Locus (genetics)|locus]] associated with [[Gilles de la Tourette syndrome|Gilles de la Tourette]] and [[Jacobsen syndrome]]s.<ref name="Lal AgarwalaGanesh2001">{{cite journal|last1=Lal Agarwala|first1=Kishan|last2=Ganesh|first2=Subramaniam|last3=Tsutsumi|first3=Yukie|last4=Suzuki|first4=Toshimitsu|last5=Amano|first5=Kenji|last6=Yamakawa|first6=Kazuhiro|s2cid=1619684|title=Cloning and Functional Characterization of DSCAML1, a Novel DSCAM-like Cell Adhesion Molecule That Mediates Homophilic Intercellular Adhesion|journal=Biochemical and Biophysical Research Communications|volume=285|issue=3|year=2001|pages=760–772|issn=0006-291X|doi=10.1006/bbrc.2001.5214|pmid=11453658|bibcode=2001BBRC..285..760L }}</ref>

Some intriguing changes in the [[gene]] structure of DSCAM have occurred in [[arthropods]] where several duplications of [[exons]] generated three large [[Tandemly arrayed genes|tandem arrays]] that are alternatively spliced.<ref name="SchmuckerClemens2000">{{cite journal|last1=Schmucker|first1=Dietmar|last2=Clemens|first2=James C|last3=Shu|first3=Huidy|last4=Worby|first4=Carolyn A|last5=Xiao|first5=Jian|last6=Muda|first6=Marco|last7=Dixon|first7=Jack E|last8=Zipursky|first8=S.Lawrence|title=Drosophila Dscam Is an Axon Guidance Receptor Exhibiting Extraordinary Molecular Diversity|journal=Cell|volume=101|issue=6|year=2000|pages=671–684|issn=0092-8674|doi=10.1016/S0092-8674(00)80878-8|pmid=10892653|doi-access=free}}</ref> This [[alternative splicing]] of individual exon sequences within an array occurs in a mutually exclusive and combinatorial manner allowing for expression of tens of thousands of Dscam [[isoforms]]. In the arthropods' genomes these three large exon arrays encode the [[N-terminus|N-terminal]] halves of the second and third Ig domains and the full Ig7 domain.<ref name="BritesMcTaggart2008"/><ref name="SchmuckerClemens2000"/><ref name="Graveley2004">{{cite journal|last1=Graveley|first1=B. R.|title=The organization and evolution of the Dipteran and Hymenopteran Down syndrome cell adhesion molecule (Dscam) genes|journal=RNA|volume=10|issue=10|year=2004|pages=1499–1506|issn=1355-8382|doi=10.1261/rna.7105504|pmid=15383675|pmc=1370636}}</ref><ref name="Watson2005">{{cite journal|last1=Watson|first1=F. L.|s2cid=10039688|title=Extensive Diversity of Ig-Superfamily Proteins in the Immune System of Insects|journal=Science|volume=309|issue=5742|year=2005|pages=1874–1878|issn=0036-8075|doi=10.1126/science.1116887|pmid=16109846|bibcode=2005Sci...309.1874W}}</ref> The different structures of these isoforms lead to differences in binding interactions. [[X-ray crystallography|Crystal structures]] of two ''D. melanogaster'' isoforms (with the first four Ig domains only), D9.9 and D1.34 ({{PDB|2V5R|2V5S}}) shows large variations in their binding [[epitopes]] and [[Protein dimer|dimerization]] interface and [[Protein conformation|conformation]]s. Much of the difference is found the Ig3 domain loop.<ref name="TsaiMa2009">{{cite journal|last1=Tsai|first1=Chung-Jung|last2=Ma|first2=Buyong|last3=Nussinov|first3=Ruth|title=Protein–protein interaction networks: how can a hub protein bind so many different partners?|journal=Trends in Biochemical Sciences|volume=34|issue=12|year=2009|pages=594–600|issn=0968-0004|doi=10.1016/j.tibs.2009.07.007|pmid=19837592|pmc=7292551}}</ref>

Comparing the [[Homology (biology)|homology]] between genes and their products, is fundamental in understanding the [[phylogenetic]] relationship across the evolutionary pathway. In addition to the thousands of isoforms that can be populated from a single DSCAM of one species, DSCAM also demonstrates a diverse array of homology across species. Below are the genes, [[Messenger RNA|mRNA]] transcripts, and proteins identified as [[Homologous chromosome|homologs]] of Down syndrome adhesion molecule.
{| class="wikitable" align="center"
|-
|+ Homologs
|-
!Species
!Gene
!mRNA
!Protein<!-- UniProt please?? -->
|-
| ''H. sapiens'' || DSCAM || NM_001389.3 || [https://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=protein&val=20127422&itool=HomoloGeneMainReport NP_001380.2]
|-
| ''P. troglodytes'' || DSCAM || XM_001171538.1 || [https://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=protein&val=114684211&itool=HomoloGeneMainReport XP_001171538.1]
|-
| ''M. mulatta'' || DSCAM || XM_002803124.1 || [https://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=protein&val=297287497&itool=HomoloGeneMainReport XP_002803170.1]
|-
| ''C. lupus'' || DSCAM || XM_544893.3 || [https://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=protein&val=345795290&itool=HomoloGeneMainReport XP_544893.3]
|-
| ''B. taurus'' || DSCAM || XM_002685111.2 || [https://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=protein&val=297471345&itool=HomoloGeneMainReport XP_002685157.1]
|-
| ''M. musculus'' || Dscam || NM_031174.4 || [https://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=protein&val=13626028&itool=HomoloGeneMainReport NP_112451.1]
|-
| ''R. norvegicus'' || Dscam || NM_133587.1 || [https://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=protein&val=19424286&itool=HomoloGeneMainReport NP_598271.1]
|-
| ''G. gallus'' || DSCAM || XM_416734.3 || [https://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=protein&val=363728871&itool=HomoloGeneMainReport XP_416734.3]
|-
| ''D. rerio'' || dscam || NM_001030224.1 || [https://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=protein&val=71834586&itool=HomoloGeneMainReport NP_001025395.1]
|-
| ''D. melanogaster'' || CG42330 || NM_001043131.2 || [https://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=protein&val=221330978&itool=HomoloGeneMainReport NP_001036596.2]
|-
| ''A. gambiae'' || AgaP_AGAP007092 || XM_308666.4 || [https://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=protein&val=158286300&itool=HomoloGeneMainReport 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 [[germline]] encoded [[pattern recognition receptors]] (PRRs), which detect different patterns associated with the molecular markers to initiate an immune response.<ref name="Smith 2011">{{cite journal|last=Smith|first=Paul|author2=Mwangi, J. |author3=Afrane, Y. |author4=Yan, G. |author5=Obbard, D. |author6=Randford-Cartwright, L. |author7=Little, T. |title=Alternative Splicing of the Anopheles Gambiae Dscam gene in Diverse Plasmodium Falciparum Infections|journal=Malaria Journal|year=2011|volume=10|page=156|doi=10.1186/1475-2875-10-156 |pmid=21651790|pmc=3118162 |doi-access=free }}</ref><ref>{{cite journal|last=R|first=Medzhitov|author2=Janeway C|title=Innate immune recognition: mechanisms and pathways|journal=Immunol Rev|year=2000|volume=173|pages=89–97|doi=10.1034/j.1600-065x.2000.917309.x|pmid=10719670|s2cid=20844121}}</ref><ref>{{cite journal|last=Christophides|first=GK|author2=Vlachou D |author3=Kafatos FC |title=Comparative and functional genomics of the innate immune system in the malaria vector Anopheles gambiae|journal=Immunol Rev|year=2004|volume=198|pages=127–148|doi=10.1111/j.0105-2896.2004.0127.x|pmid=15199960|s2cid=6188654|doi-access=free}}</ref><ref>{{cite journal|last=Akira|first=S|author2=Takeda K|title=Toll-like receptor signalling|journal=Nat Rev Immunol|year=2004|volume=4|issue=7|pages=499–511|doi=10.1038/nri1391|pmid=15229469|s2cid=23467641}}</ref><ref>{{cite journal|last=Christensen|first=BM|author2=Li JY |author3=Chen CC |author4=Nappi AJ |title=Melanization immune responses in mosquito vectors|journal=Trends Parasitol|year=2005|volume=21|issue=4|pages=191–199|doi=10.1016/j.pt.2005.02.007|pmid=15780842}}</ref> The role of Dscam in the fly immune response was demonstrated by an [[RNAi]] mediated depletion experiment of DSCAM in which it was found to be associated with the cells that play a role in the fly's immune system.<ref name="Smith 2011"/><ref>{{cite journal|last=Watson|first=FL|author2=Puttmann-Holgado R |author3=Thomas F |author4=Lamar DL |author5=Hughes M |author6=Kondo M |author7=Rebel VI |author8=Schmucker D |s2cid=10039688|title=Extensive diversity of Ig-superfamily proteins in the immune system of insects|journal=Science|year=2005|volume=309|pages=1874–1878|doi=10.1126/science.1116887|pmid=16109846 |issue=5742|bibcode=2005Sci...309.1874W}}</ref>

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]].<ref name="Smith 2011"/><ref>{{cite journal|last=Dong|first=YM|author2=Taylor HE |author3=Dimopoulos G |title=AgDscam, a hypervariable immunoglobulin domain-containing receptor of the Anopheles gambiae innate immune system|journal=PLOS Biology|year=2006|volume=4|issue=7|pages=1137–1146|doi=10.1371/journal.pbio.0040229|pmid=16774454|pmc=1479700 |doi-access=free }} {{open access}}</ref>

===Regulation of synaptogenesis===
Self-avoidance is a mechanism where the [[neuronal process]]es from the cell repel each other during arborization and axon branching to avoid [[fasciculation]] and clumping. Self-avoidance is necessary to prevent extensive overlapping in the arborization pattern and to facilitate the coverage of the neuronal processes across different regions of the nervous system during development.

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 [[immunoglobulin superfamily]] bind homophilically and specifically.<ref name="Garrett">{{cite journal|last=Garrett|first=Andrew M.|author2=Tadenev, Abigail L. D. |author3=Burgess, Robert W. |title=DSCAMs: restoring balance to developmental forces|journal=Frontiers in Molecular Neuroscience|date=1 January 2012|volume=5|pages=86|series=5|doi=10.3389/fnmol.2012.00086|pmid=22912601|pmc=3421437|doi-access=free }}</ref><ref>{{cite journal|last=Lal Agarwala|first=Kishan|author2=Ganesh, Subramaniam |author3=Tsutsumi, Yukie |author4=Suzuki, Toshimitsu |author5=Amano, Kenji |author6= Yamakawa, Kazuhiro |s2cid=1619684|title=Cloning and Functional Characterization of DSCAML1, a Novel DSCAM-like Cell Adhesion Molecule That Mediates Homophilic Intercellular Adhesion|journal=Biochemical and Biophysical Research Communications|date=1 July 2001|volume=285|issue=3|pages=760–772|doi=10.1006/bbrc.2001.5214 |pmid=11453658|bibcode=2001BBRC..285..760L }}</ref><ref>{{cite journal|last=Agarwala|first=Kishan Lal|author2=Nakamura, Sawako |author3=Tsutsumi, Yukie |author4= Yamakawa, Kazuhiro |title=Down syndrome cell adhesion molecule DSCAM mediates homophilic intercellular adhesion|journal=Molecular Brain Research|date=1 June 2000|volume=79|issue=1–2|pages=118–126|doi=10.1016/S0169-328X(00)00108-X |pmid=10925149}}</ref><ref>{{cite journal|last=Yamagata|first=Masahito|author2=Sanes, Joshua R.|title=Dscam and Sidekick proteins direct lamina-specific synaptic connections in vertebrate retina|journal=Nature|date=24 January 2008|volume=451|issue=7177|pages=465–469|doi=10.1038/nature06469|pmid=18216854|bibcode=2008Natur.451..465Y|doi-access=free}}</ref> These molecules also appear to have a role in [[chemoattraction]] and repulsion.

Dscam1, of ''drosophila'', may be one of the molecules involved in counteracting the [[netrin]]-dependent chemoattraction between neuronal processes during the neural development stage.<ref name="Garrett"/> As previously mentioned, the Dscam1 gene in ''drosophila'' can encode 19008 [[extracellular domain]]s, which bind homophilically and with isoform specificity.<ref>{{cite journal|last=Wojtowicz|first=Woj M.|author2=Flanagan, John J. |author3=Millard, S.Sean |author4=Zipursky, S.Lawrence |author5= Clemens, James C. |title=Alternative Splicing of Drosophila Dscam Generates Axon Guidance Receptors that Exhibit Isoform-Specific Homophilic Binding|journal=Cell|date=1 September 2004|volume=118|issue=5|pages=619–633|doi=10.1016/j.cell.2004.08.021|pmid=15339666|pmc=2691713}}</ref> The isoform-specific binding properties of Dscam, during homophilic repulsion, are the basis of self-avoidance, which is a crucial developmental mechanism for uniform distribution of axonal and dendritic processes in the formation of synaptic fields.<ref name="Hattori" /> The neurons express a stochastic array of Dscam1 isoforms on their cell surface. Cells that have the same isoform patterns displaced on their surface, recognize the other as 'self', which leads to self-avoidance with the processes of neurons of the same subtype homophilically repelling from each other.

In addition to homophilic repulsion, Dscam1 mediates repulsion between [[neurites]] of different subtypes based on the specific isoform patterns displayed on the cell surface. This is called cell-type specific avoidance. The [[photoreceptor cell|photoreceptor]] terminals of Drosophila form synapses with the postsynaptic invariant ([[Tetrad (chromosomal formation)|tetrad]]) synapses that connect a pair of postsynaptic elements. Dscam is thought to aid this process by regulating the synaptic specificity through exclusion of inappropriate synaptic combination at the contact site.<ref name="Millard 761–768">{{cite journal|last=Millard|first=S. Sean|author2=Lu, Zhiyuan |author3=Zipursky, S. Lawrence |author4= Meinertzhagen, Ian A. |title=Drosophila Dscam Proteins Regulate Postsynaptic Specificity at Multiple-Contact Synapses|journal=Neuron|date=9 September 2010|volume=67|issue=5|pages=761–768|doi=10.1016/j.neuron.2010.08.030 |pmid=20826308 |pmc=3307816}}</ref>

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.<ref>{{cite journal|last=Grueber|first=W. B.|author2=Sagasti, A.|title=Self-avoidance and Tiling: Mechanisms of Dendrite and Axon Spacing|journal=Cold Spring Harbor Perspectives in Biology|date=23 June 2010|volume=2|issue=9|pages=a001750|doi=10.1101/cshperspect.a001750|pmid=20573716|pmc=2926746}}</ref> Dscam1 and Dscam2 appear to be involved in axonal branching and tiling in Drosophila.<ref>{{cite journal|last=Wang|first=J|author2=Zugates, CT |author3=Liang, IH |author4=Lee, CH |author5= Lee, T |title=Drosophila Dscam is required for divergent segregation of sister branches and suppresses ectopic bifurcation of axons.|journal=Neuron|date=14 February 2002|volume=33|issue=4|pages=559–71|pmid=11856530|doi=10.1016/S0896-6273(02)00570-6|doi-access=free}}</ref><ref>{{cite journal|last=Millard|first=SS|author2=Flanagan, JJ |author3=Pappu, KS |author4=Wu, W |author5= Zipursky, SL |title=Dscam2 mediates axonal tiling in the Drosophila visual system.|journal=Nature|date=7 June 2007|volume=447|issue=7145|pages=720–4|pmid=17554308|doi=10.1038/nature05855|pmc=2691714|bibcode=2007Natur.447..720M}}</ref> Tiling occurs when homophilic repulsion mediated by Dscam2 prevents the processes of the same class of cells from overlapping.<ref name="Hattori"/> While both Dscam1 and Dscam2 mediate homophilic repulsion, the Dscam2 gene (unlike Dscam1) only encodes two alternative isoforms and thus lacks possible molecular diversity.<ref name="Millard 761–768"/> 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.<ref name="Millard 761–768"/>

==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),<ref name="AgarwalaNakamura2000">{{cite journal|last1=Agarwala|first1=Kishan Lal|last2=Nakamura|first2=Sawako|last3=Tsutsumi|first3=Yukie|last4=Yamakawa|first4=Kazuhiro|title=Down syndrome cell adhesion molecule DSCAM mediates homophilic intercellular adhesion|journal=Molecular Brain Research|volume=79|issue=1–2|year=2000|pages=118–126|issn=0169-328X|doi=10.1016/S0169-328X(00)00108-X|pmid=10925149}}</ref><ref name="YamagataSanes2008">{{cite journal|last1=Yamagata|first1=Masahito|last2=Sanes|first2=Joshua R.|title=Dscam and Sidekick proteins direct lamina-specific synaptic connections in vertebrate retina|journal=Nature|volume=451|issue=7177|year=2008|pages=465–469|issn=0028-0836|doi=10.1038/nature06469|pmid=18216854|bibcode=2008Natur.451..465Y|doi-access=free}}</ref> but also have cell-type specific, mutually exclusive, expression patterns.<ref name="YamagataSanes2008"/><ref name="BarlowMicales2002">{{cite journal|last1=Barlow|first1=Gillian M|last2=Micales|first2=Bruce|last3=Chen|first3=Xiao-Ning|last4=Lyons|first4=Gary E|last5=Korenberg|first5=Julie R|title=Mammalian DSCAMs: roles in the development of the spinal cord, cortex, and cerebellum?|journal=Biochemical and Biophysical Research Communications|volume=293|issue=3|year=2002|pages=881–891|issn=0006-291X|doi=10.1016/S0006-291X(02)00307-8|pmid=12051741|bibcode=2002BBRC..293..881B }}</ref> Due to the combinatorial use of alternative exons, the homophilic binding specificity of Drosophila Dscam is amplified to tens of thousands of potential [[Protein dimer|homodimers]].,<ref name="WojtowiczFlanagan2004">{{cite journal|last1=Wojtowicz|first1=Woj M.|last2=Flanagan|first2=John J.|last3=Millard|first3=S.Sean|last4=Zipursky|first4=S.Lawrence|last5=Clemens|first5=James C.|title=Alternative Splicing of Drosophila Dscam Generates Axon Guidance Receptors that Exhibit Isoform-Specific Homophilic Binding|journal=Cell|volume=118|issue=5|year=2004|pages=619–633|issn=0092-8674|doi=10.1016/j.cell.2004.08.021|pmid=15339666|pmc=2691713}}</ref><ref name="WojtowiczWu2007">{{cite journal|last1=Wojtowicz|first1=Woj M.|last2=Wu|first2=Wei|last3=Andre|first3=Ingemar|last4=Qian|first4=Bin|last5=Baker|first5=David|last6=Zipursky|first6=S. Lawrence|title=A Vast Repertoire of Dscam Binding Specificities Arises from Modular Interactions of Variable Ig Domains|journal=Cell|volume=130|issue=6|year=2007|pages=1134–1145|issn=0092-8674|doi=10.1016/j.cell.2007.08.026|pmid=17889655|pmc=2707357}}</ref> [[Assay|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.<ref name="SchmuckerChen2009"/>

==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<ref name="Yamakawa1998"/><ref name="BarlowMicales2001">{{cite journal|last1=Barlow|first1=G.M.|last2=Micales|first2=B.|last3=Lyons|first3=G.E.|last4=Korenberg|first4=J.R.|title=Down Syndrome Cell Adhesion Molecule is conserved in mouse and highly expressed in the adult mouse brain|journal=Cytogenetic and Genome Research|volume=94|issue=3–4|year=2001|pages=155–162|issn=1424-859X|doi=10.1159/000048808|pmid=11856873|s2cid=34420016}}</ref> and DSCAML1 maps to chromosome 11 in a region whose deletion is associated with [[Jacobsen syndrome|11q deletion syndrome]]. This gives rise to neurocognitive defects and a subset of other defects which are similar to those seen in DS, including [[psychomotor retardation]], [[Strabismus]], [[Epicanthus]], [[Telecanthus]], carp-shaped upper lip, low-set [[Dysmorphic feature|dysmorphic]] ears, and cardiac defects.<ref name="BarlowMicales2002"/><ref>{{cite book|last=Epstein|first=C.J.|title= The Consequences of Chromosomal Imbalance |publisher= Cambridge University Press |year=1986}}</ref> The level of DSCAM expression is increased by more than 20% in the DS brain.<ref name="BahnMimmack2002">{{cite journal|last1=Bahn|first1=Sabine|last2=Mimmack|first2=Michael|last3=Ryan|first3=Margaret|last4=Caldwell|first4=Maeve A|last5=Jauniaux|first5=Eric|last6=Starkey|first6=Michael|last7=Svendsen|first7=Clive N|last8=Emson|first8=Piers|title=Neuronal target genes of the neuron-restrictive silencer factor in neurospheres derived from fetuses with Down's syndrome: a gene expression study|journal=The Lancet|volume=359|issue=9303|year=2002|pages=310–315|issn=0140-6736|doi=10.1016/S0140-6736(02)07497-4|pmid=11830198|s2cid=26101684}}</ref> Given its identity as a potential neural [[morphogen]] and its expression in the [[Cerebrum|cerebral]] and [[Cerebellum|cerebellar]] cortices from the earliest stages in their development, it is not unreasonable to suggest that this level of DSCAM over-expression may contribute to the pre- and post-natal defects of DS, particularly, the cerebral and cerebellar hypoplasia and the abnormalities of the [[Dendrite|dendritic tree]].<ref name="SchmuckerChen2009"/><ref name="RazTorres1995">{{cite journal|last1=Raz|first1=N.|last2=Torres|first2=I. J.|last3=Briggs|first3=S. D.|last4=Spencer|first4=W. D.|last5=Thornton|first5=A. E.|last6=Loken|first6=W. J.|last7=Gunning|first7=F. M.|last8=McQuain|first8=J. D.|last9=Driesen|first9=N. R.|last10=Acker|first10=J. D.|title=Selective neuroanatornic abnormalities in Down's syndrome and their cognitive correlates: Evidence from MRI morphometry|journal=Neurology|volume=45|issue=2|year=1995|pages=356–366|issn=0028-3878|doi=10.1212/WNL.45.2.356|pmid=7854539|s2cid=13559183}}</ref> Further, a role for DSCAM over-expression in contributing to the defects of cortical lamination seen in DS<ref name="pmid8083693">{{cite journal|vauthors=Golden JA, Hyman BT | title=Development of the superior temporal neocortex is anomalous in trisomy 21. | journal=J Neuropathol Exp Neurol | year= 1994 | volume= 53 | issue= 5 | pages= 513–20 | pmid=8083693 | doi= 10.1097/00005072-199409000-00011| s2cid=23392950 }}</ref> is supported by the fact that disruptions in other genes expressed by [[Cajal–Retzius cell]]s, such as [[Reelin]] and [[PAFAH1B1|LIS1]], cause severe defects in [[neuroblast]] migration and cortical lamination.<ref name="pmid7748558">{{cite journal|vauthors=Ogawa M, Miyata T, Nakajima K, Yagyu K, Seike M, Ikenaka K | title=The reeler gene-associated antigen on Cajal-Retzius neurons is a crucial molecule for laminar organization of cortical neurons. | journal=Neuron | year= 1995 | volume= 14 | issue= 5 | pages= 899–912 | pmid=7748558 | doi= 10.1016/0896-6273(95)90329-1|display-authors=etal| doi-access= free }}</ref><ref name="pmid10220225">{{cite journal|vauthors=Noctor SC, Palmer SL, Hasling T, Juliano SL | title=Interference with the development of early generated neocortex results in disruption of radial glia and abnormal formation of neocortical layers. | journal=Cereb Cortex | year= 1999 | volume= 9 | issue= 2 | pages= 121–36 | pmid=10220225 | doi= 10.1093/cercor/9.2.121| doi-access= free }}</ref>

A study of [[congenital heart defect]] (CHD) investigated the [[polygene|polygenic]] effect of DSCAM with other genes. Under normal physiological conditions, DSCAM and [[COL6A2]] work jointly in the drosophila to mediate cell matrix adhesion. However, over-expressing DSCAM and COL6A2 in the drosophila and mouse heart, resulted in a high mortality rate in addition to several serious heart defects, including atrial [[Septum|septal]] defects and cardiac [[hypertrophy]]. The interaction between DSCAM and [[COL6A2]] and their combined effects were also observed in the H9c2 cardiac cell line with incidence of [[cardiac hypertrophy]]. While other gene combinations were screened to test the polygenic effect on the cardiac disorder, the DSCAM&nbsp;– COL6A2 pair was found to cause the most severe adverse effect in drosophila.<ref>{{cite journal|last=Grossman|first=Tamar R.|author2=Gamliel, Amir |author3=Wessells, Robert J. |author4=Taghli-Lamallem, Ouarda |author5=Jepsen, Kristen |author6=Ocorr, Karen |author7=Korenberg, Julie R. |author8=Peterson, Kirk L. |author9=Rosenfeld, Michael G. |author10=Bodmer, Rolf |author11=Bier, Ethan |author12=Barsh, Gregory S. |title=Over-Expression of DSCAM and COL6A2 Cooperatively Generates Congenital Heart Defects|journal=PLOS Genetics|date=3 November 2011|volume=7|issue=11|pages=e1002344|doi=10.1371/journal.pgen.1002344 |pmid=22072978 |pmc=3207880 |doi-access=free }} {{open access}}</ref> Translating the result to human cases of heart defects in DS patients require more study due to species-specific variance in the gene expression level. Nonetheless, the finding that DSCAM exerts a synergistic effect on the cardiac disease progression, upon disrupted expression level, allows future research on its role in some other major diseases.

== See also ==
* [[IgSF CAM]]

==References==
{{reflist|2}}

==Additional sources==
{{refbegin}}
#{{cite journal |vauthors=Wojtowicz WM, Flanagan JJ, Millard SS, Zipursky SL, Clemens JC |title=Alternative splicing of Drosophila Dscam generates axon guidance receptors that exhibit isoform-specific homophilic binding |journal=Cell |volume=118 |issue=5 |pages=619–33 |date=September 2004 |pmid=15339666 |pmc=2691713 |doi=10.1016/j.cell.2004.08.021 }}
#{{cite journal |vauthors=Watson FL, Püttmann-Holgado R, Thomas F |s2cid=10039688 |title=Extensive diversity of Ig-superfamily proteins in the immune system of insects |journal=Science |volume=309 |issue=5742 |pages=1874–8 |date=September 2005 |pmid=16109846 |doi=10.1126/science.1116887 |bibcode=2005Sci...309.1874W |display-authors=etal}}
#{{cite journal |vauthors=Chen BE, Kondo M, Garnier A |title=The molecular diversity of Dscam is functionally required for neuronal wiring specificity in Drosophila |journal=Cell |volume=125 |issue=3 |pages=607–20 |date=May 2006 |pmid=16678102 |doi=10.1016/j.cell.2006.03.034 |display-authors=etal|doi-access=free }}
{{refend}}

[[Category:Proteins]]