Further Development 3.14: The DSCAM Gene and its 38,016 Isoforms

Differential Gene Expression: Mechanisms of Cell Differentiation

If you have gotten the impression from the above discussion that one gene with dozens of introns could create thousands of different but related proteins through differential splicing, then you would be correct, at least in the case of Dscam. The current champion at making multiple proteins from the same gene is the Drosophila Dscam gene.1 This gene encodes a membrane adhesion protein that prevents dendrites from the same neuron from touching (Wu et al. 2012). Dscam contains 115 exons. Moreover, a dozen different adjacent DNA sequences can be selected to be exon 4, and nearly 3 to 4 dozen mutually exclusive adjacent DNA sequences can become exons 6 and 9 (Figure 1A; Schmucker et al. 2000). If all possible combinations of exons are used, this one gene can produce 38,016 different proteins, and random searches for these combinations indicate that a large fraction of them are, in fact, made. The pre-mRNA of Dscam has been found to be alternatively spliced in different neurons, and when two dendrites from the same Dscam-expressing neuron touch each other, they are repelled (Figure 1B; Wu et al. 2012). This repulsion promotes the extensive branching of the dendrites and ensures that axon-dendrite synapses occur appropriately between neurons. It appears that the thousands of splicing isoforms are needed to ensure that each neuron acquires a unique identity (Figure 1C; Schmucker 2007; Millard and Zipursky 2008; Miura et al. 2013). Moreover, the combination of expressed Dscam1 isoforms can change in a given neuron with each new round of RNA synthesis. Such timely changes in alternative splicing may be in response to neuron-neuron interactions during the process of dendritic arborization. The Drosophila genome is thought to contain only 14,000 genes, but here is a single gene that encodes nearly three times that number of proteins!

1 DSCAM (Down syndrome cell adhesion molecule) is a gene found in humans within the “Down syndrome” region of chromosome 21. It encodes a cell adhesion molecule that functions through homophilic binding and is important for axon guidance.

Figure 1 The Dscam gene of Drosophila can produce 38,016 different proteins by alternative pre-mRNA splicing. (A) The gene contains 24 exons. Exons 4, 6, 9, and 17 are encoded by sets of mutually exclusive possible sequences. Each messenger RNA will contain one of the 12 possible exon 4 sequences, one of the 48 possible exon 6 alternatives, one of the 33 possible exon 9 alternatives, and one of the 2 possible exon 17 sequences. The Drosophila Dscam gene is homologous to a DNA sequence on human chromosome 21 that is expressed in the nervous system. Disturbances of this gene in humans may contribute to the neurological defects of Down syndrome. (B) Dscam is required for self-avoidance between dendrites that fosters a dispersed pattern of dendrites (left). Loss of Dscam in Drosophila, however, causes crossing and fasciculated growth of dendrites from the same neuron (right; arrows). (C) Expression of alternatively spliced forms of Dscam (4.1, 4.2, 4.9, and 4.12) in isolated populations of mushroom body neurons (white) in midpupal brains of the fly. The full mushroom body lobes and associated Kenyon cells are seen with antibodies to anti-Fasciclin II and anti-Dachshund, respectively (blue). (A after D. Schmucker et al. 2000. Cell 101: 671–684.)

Developing Questions

About 92% of human genes are thought to produce multiple types of mRNA. Therefore, even though the human genome may contain about 20,000 genes, its proteome—the number and type of proteins encoded by the genome—is far larger and more complex. “Human genes are multitaskers,” notes Christopher Burge, one of the scientists who calculated this figure (Ledford 2008). This fact explains an important paradox. Homo sapiens has about 20,000 genes in each nucleus; so does the nematode C. elegans, a tubular creature with only 959 cells. We have more cells and cell types in the shaft of a hair than C. elegans has in its entire body. What’s this worm doing with approximately the same number of genes that we have?

Literature Cited

Millard, S. S. and S. L. Zipursky. 2008. Dscam-mediated repulsion controls tiling and self-avoidance. Curr. Opin. Neurobiol. 18: 84–89.
PubMed Link

Miura, S. K., A. Martins, K. X. Zhang, B. R. Graveley and S. L. Zipursky. 2013. Probabilistic splicing of Dscam1 establishes identity at the level of single neurons. Cell 155: 1166–1177.
PubMed Link

Schmucker, D. 2007. Molecular diversity of Dscam: Recognition of molecular identity in neuronal wiring. Nat. Rev. Neurosci. 8: 915–920.
PubMed Link

Schmucker, D., J. C. Clemens, H. Shu, C. A. Worby, J. Xiao, M. Muda, J. E. Dixon, and S. L. Zipursky. 2000. Drosophila Dscam is an axon guidance receptor exhibiting extraordinary molecular diversity. Cell 101: 671–684.
PubMed Link

Wu, W., G. Ahlsen, D. Baker, L. Shapiro, and L. Zipursky. 2012. Complementary chimeric isoforms reveal Dscam1 binding specificity in vivo. Neuron 74: 261–268.
PubMed Link

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