DSCAM

Last updated

DSCAM
Identifiers
Aliases DSCAM , CHD2-42, CHD2-52, CHD2, DS cell adhesion molecule
External IDs OMIM: 602523 MGI: 1196281 HomoloGene: 74393 GeneCards: DSCAM
Orthologs
SpeciesHumanMouse
Entrez

1826

13508

Ensembl

ENSG00000171587

ENSMUSG00000050272

UniProt

O60469

Q9ERC8

RefSeq (mRNA)

NM_001271534
NM_001389

NM_031174

RefSeq (protein)

NP_001258463
NP_001380

NP_112451

Location (UCSC) Chr 21: 40.01 – 40.85 Mb Chr 16: 96.59 – 97.17 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse
Down syndrome cell adhesion molecule, chordates
Identifiers
SymbolDSCAM_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]

Contents

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 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 deuterostomes and protostomes, and assuming an ancestral homologous gene, places the origin of the DSCAM gene at >600 million years ago. Since then, the DSCAM gene has been duplicated at least once in vertebrates and insects. [9] [10]

DSCAM was first identified in an effort to characterize proteins located within human chromosome band 21q22, a region known to play a critical role in Down syndrome. [11] 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 related to other cell adhesion molecules (CAMs). [12]

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, DSCAML1, is located on chromosome band 11q23, a locus associated with Gilles de la Tourette and Jacobsen syndromes. [14]

Some intriguing changes in the gene structure of DSCAM have occurred in arthropods where several duplications of exons generated three large tandem arrays that are alternatively spliced. [15] 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-terminal halves of the second and third Ig domains and the full Ig7 domain. [10] [15] [16] [17] The different structures of these isoforms lead to differences in binding interactions. 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 dimerization interface and conformations. Much of the difference is found the Ig3 domain loop. [18]

Comparing the 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, mRNA transcripts, and proteins identified as homologs of Down syndrome adhesion molecule.

Homologs
SpeciesGenemRNAProtein
H. sapiensDSCAMNM_001389.3 NP_001380.2
P. troglodytesDSCAMXM_001171538.1 XP_001171538.1
M. mulattaDSCAMXM_002803124.1 XP_002803170.1
C. lupusDSCAMXM_544893.3 XP_544893.3
B. taurusDSCAMXM_002685111.2 XP_002685157.1
M. musculusDscamNM_031174.4 NP_112451.1
R. norvegicusDscamNM_133587.1 NP_598271.1
G. gallusDSCAMXM_416734.3 XP_416734.3
D. reriodscamNM_001030224.1 NP_001025395.1
D. melanogasterCG42330NM_001043131.2 NP_001036596.2
A. gambiaeAgaP_AGAP007092XM_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 germline encoded pattern recognition receptors (PRRs), which detect different patterns associated with the molecular markers to initiate an immune response. [19] [20] [21] [22] [23] 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. [19] [24]

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 neuronal processes 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. [26] [27] [28] [29] 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. [26] As previously mentioned, the Dscam1 gene in drosophila can encode 19008 extracellular domains, which bind homophilically and with isoform specificity. [30] 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. [8] 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 terminals of Drosophila form synapses with the postsynaptic invariant (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. [31]

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 [11] [40] and DSCAML1 maps to chromosome 11 in a region whose deletion is associated with 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 ears, and cardiac defects. [37] [41] The level of DSCAM expression is increased by more than 20% in the DS brain. [42] Given its identity as a potential neural morphogen and its expression in the cerebral and 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 dendritic tree. [12] [43] Further, a role for DSCAM over-expression in contributing to the defects of cortical lamination seen in DS [44] is supported by the fact that disruptions in other genes expressed by Cajal–Retzius cells, such as Reelin and LIS1, cause severe defects in neuroblast migration and cortical lamination. [45] [46]

A study of congenital heart defect (CHD) investigated the 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 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 – COL6A2 pair was found to cause the most severe adverse effect in drosophila. [47] 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

Related Research Articles

<span class="mw-page-title-main">Cell adhesion</span> Process of cell attachment

Cell adhesion is the process by which cells interact and attach to neighbouring cells through specialised molecules of the cell surface. This process can occur either through direct contact between cell surfaces such as cell junctions or indirect interaction, where cells attach to surrounding extracellular matrix, a gel-like structure containing molecules released by cells into spaces between them. Cells adhesion occurs from the interactions between cell-adhesion molecules (CAMs), transmembrane proteins located on the cell surface. Cell adhesion links cells in different ways and can be involved in signal transduction for cells to detect and respond to changes in the surroundings. Other cellular processes regulated by cell adhesion include cell migration and tissue development in multicellular organisms. Alterations in cell adhesion can disrupt important cellular processes and lead to a variety of diseases, including cancer and arthritis. Cell adhesion is also essential for infectious organisms, such as bacteria or viruses, to cause diseases.

Synaptogenesis is the formation of synapses between neurons in the nervous system. Although it occurs throughout a healthy person's lifespan, an explosion of synapse formation occurs during early brain development, known as exuberant synaptogenesis. Synaptogenesis is particularly important during an individual's critical period, during which there is a certain degree of synaptic pruning due to competition for neural growth factors by neurons and synapses. Processes that are not used, or inhibited during their critical period will fail to develop normally later on in life.

Cell adhesion molecules (CAMs) are a subset of cell surface proteins that are involved in the binding of cells with other cells or with the extracellular matrix (ECM), in a process called cell adhesion. In essence, CAMs help cells stick to each other and to their surroundings. CAMs are crucial components in maintaining tissue structure and function. In fully developed animals, these molecules play an integral role in generating force and movement and consequently ensuring that organs are able to execute their functions normally. In addition to serving as "molecular glue", CAMs play important roles in the cellular mechanisms of growth, contact inhibition, and apoptosis. Aberrant expression of CAMs may result in a wide range of pathologies, ranging from frostbite to cancer.

<span class="mw-page-title-main">L1 (protein)</span> Mammalian protein found in Homo sapiens

L1, also known as L1CAM, is a transmembrane protein member of the L1 protein family, encoded by the L1CAM gene. This protein, of 200-220 kDa, is a neuronal cell adhesion molecule with a strong implication in cell migration, adhesion, neurite outgrowth, myelination and neuronal differentiation. It also plays a key role in treatment-resistant cancers due to its function. It was first identified in 1984 by M. Schachner who found the protein in post-mitotic mice neurons.

<span class="mw-page-title-main">Neural cell adhesion molecule</span> Mammalian protein found in Homo sapiens

Neural cell adhesion molecule (NCAM), also called CD56, is a homophilic binding glycoprotein expressed on the surface of neurons, glia and skeletal muscle. Although CD56 is often considered a marker of neural lineage commitment due to its discovery site, CD56 expression is also found in, among others, the hematopoietic system. Here, the expression of CD56 is mostly associated with, but not limited to, natural killer cells. CD56 has been detected on other lymphoid cells, including gamma delta (γδ) Τ cells and activated CD8+ T cells, as well as on dendritic cells. NCAM has been implicated as having a role in cell–cell adhesion, neurite outgrowth, synaptic plasticity, and learning and memory.

Axon guidance is a subfield of neural development concerning the process by which neurons send out axons to reach their correct targets. Axons often follow very precise paths in the nervous system, and how they manage to find their way so accurately is an area of ongoing research.

<span class="mw-page-title-main">CD31</span> Mammalian protein found in Homo sapiens

Platelet endothelial cell adhesion molecule (PECAM-1) also known as cluster of differentiation 31 (CD31) is a protein that in humans is encoded by the PECAM1 gene found on chromosome17q23.3. PECAM-1 plays a key role in removing aged neutrophils from the body.

<span class="mw-page-title-main">Protocadherin</span>

Protocadherins (Pcdhs) are the largest mammalian subgroup of the cadherin superfamily of homophilic cell-adhesion proteins. They were discovered by Shintaro Suzuki's group, when they used PCR to find new members of the cadherin family. The PCR fragments that corresponded to protocadherins were found in vertebrate and invertebrate species. This prevalence in a wide range of species suggested that the fragments were part of an ancient cadherin and were thus termed "Protocadherins" as the "first cadherins". Of the approximately 70 Pcdh genes identified in mammalian genomes, over 50 are located in tightly linked gene clusters on the same chromosome. Until recently, it was assumed that this kind of organization can only be found in vertebrates, but Octopus bimaculoides has 168 genes of which nearly three-quarters are found in tandem clusters with the two largest clusters compromising 31 and 17 genes, respectively.

<span class="mw-page-title-main">Neurexin</span> Protein family

Neurexins (NRXN) are a family of presynaptic cell adhesion proteins that have roles in connecting neurons at the synapse. They are located mostly on the presynaptic membrane and contain a single transmembrane domain. The extracellular domain interacts with proteins in the synaptic cleft, most notably neuroligin, while the intracellular cytoplasmic portion interacts with proteins associated with exocytosis. Neurexin and neuroligin "shake hands," resulting in the connection between the two neurons and the production of a synapse. Neurexins mediate signaling across the synapse, and influence the properties of neural networks by synapse specificity. Neurexins were discovered as receptors for α-latrotoxin, a vertebrate-specific toxin in black widow spider venom that binds to presynaptic receptors and induces massive neurotransmitter release. In humans, alterations in genes encoding neurexins are implicated in autism and other cognitive diseases, such as Tourette syndrome and schizophrenia.

<span class="mw-page-title-main">CEACAM1</span> Mammalian protein found in Homo sapiens

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) also known as CD66a, is a human glycoprotein, and a member of the carcinoembryonic antigen (CEA) gene family.

<span class="mw-page-title-main">Contactin 2</span> Protein found in humans

Contactin-2 is a protein that in humans is encoded by the CNTN2 gene.

<span class="mw-page-title-main">PTPRM</span> Protein-coding gene in the species Homo sapiens

Receptor-type tyrosine-protein phosphatase mu is an enzyme that in humans is encoded by the PTPRM gene.

<span class="mw-page-title-main">PTPRU</span> Protein-coding gene in the species Homo sapiens

Receptor-type tyrosine-protein phosphatase PCP-2, is an enzyme that in humans is encoded by the PTPRU gene.

<span class="mw-page-title-main">PTPRT</span> Protein-coding gene in the species Homo sapiens

Receptor-type tyrosine-protein phosphatase T is an enzyme that in humans is encoded by the PTPRT gene.

<span class="mw-page-title-main">ROBO2</span> Protein-coding gene in the species Homo sapiens

Roundabout homolog 2 is a protein that in humans is encoded by the ROBO2 gene.

<span class="mw-page-title-main">Neuroligin</span> Protein

Neuroligin (NLGN), a type I membrane protein, is a cell adhesion protein on the postsynaptic membrane that mediates the formation and maintenance of synapses between neurons. Neuroligins act as ligands for β-neurexins, which are cell adhesion proteins located presynaptically. Neuroligin and β-neurexin "shake hands", resulting in the connection between two neurons and the production of a synapse. Neuroligins also affect the properties of neural networks by specifying synaptic functions, and they mediate signalling by recruiting and stabilizing key synaptic components. Neuroligins interact with other postsynaptic proteins to localize neurotransmitter receptors and channels in the postsynaptic density as the cell matures. Additionally, neuroligins are expressed in human peripheral tissues and have been found to play a role in angiogenesis. In humans, alterations in genes encoding neuroligins are implicated in autism and other cognitive disorders. Antibodies in a mother from previous male pregnancies against neuroligin 4 from the Y chromosome increase the probability of homosexuality in male offspring.

<span class="mw-page-title-main">Roundabout family</span>

The Roundabout (Robo) family of proteins are single-pass transmembrane receptors that are highly conserved across many branches of the animal kingdom, from C. elegans to humans. They were first discovered in Drosophila, through a mutant screen for genes involved in axon guidance. The Drosophila roundabout mutant was named after its phenotype, which resembled the circular traffic junctions. The Robo receptors are most well known for their role in the development of the nervous system, where they have been shown to respond to secreted Slit ligands. One well-studied example is the requirement for Slit-Robo signaling in regulation of axonal midline crossing. Slit-Robo signaling is also critical for many neurodevelopmental processes including formation of the olfactory tract, the optic nerve, and motor axon fasciculation. In addition, Slit-Robo signaling contributes to cell migration and the development of other tissues such as the lung, kidney, liver, muscle and breast. Mutations in Robo genes have been linked to multiple neurodevelopmental disorders in humans.

<span class="mw-page-title-main">CD96</span> Protein-coding gene in the species Homo sapiens

CD96 or Tactile is a protein that in humans is encoded by the CD96 gene. CD96 is a receptor protein which is expressed on T cells and NK cells and shares sequence similarity with CD226. The protein encoded by this gene belongs to the immunoglobulin superfamily. It is a type I membrane protein. The protein may play a role in the adhesion of activated T and NK cells to their target cells during the late phase of the immune response. It may also function in antigen presentation. Alternative splicing occurs at this locus and two transcript variants encoding distinct isoforms have been identified. CD96 is a transmembrane glycoprotein that has three extracellular immunoglobulin-like domains and is expressed by all resting human and mouse NK cells. CD96 main ligand is CD155. CD 96 has approximately 20% homology with CD226 and competed for binding to CD155 with CD226.

<span class="mw-page-title-main">Neuronal self-avoidance</span>

Neuronal self-avoidance, or isoneural avoidance, is an important property of neurons which consists in the tendency of branches arising from a single soma to turn away from one another. The arrangements of branches within neuronal arbors are established during development and result in minimal crossing or overlap as they spread over a territory, resulting in the typical fasciculated morphology of neurons.

<span class="mw-page-title-main">Nectin-3</span>

Nectin-3, also known as nectin cell adhesion molecule 3, is a protein that in humans is encoded by the NECTIN3 gene.

References

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