Down syndrome cell adhesion molecule, or Dscam, is a protein found in various animals, including humans and fruit flies. It functions as a cell adhesion molecule, helping cells recognize and stick to each other. Dscam is involved in biological processes, playing roles in the organization of the nervous system and the immune system.
Generating Immense Diversity
Dscam’s ability to generate a vast array of protein versions from a single gene is achieved through alternative splicing. A gene can be thought of as a recipe book, with “exons” as sections containing instructions. Alternative splicing allows cells to pick and choose which exons to include in the final protein, much like selecting different ingredients.
The fruit fly, Drosophila melanogaster, is a key example of this diversity, with its Dscam gene can produce 38,016 distinct protein isoforms. This number comes from four variable exon clusters, containing 12, 48, 33, and 2 alternative exons, respectively. Each resulting protein isoform has a unique sequence in specific regions, even though they share a common overall structure. The human equivalent gene, DSCAM, also exists, though it does not exhibit the same extensive alternative splicing seen in insects.
Shaping the Nervous System
Dscam plays an important role in the wiring of the nervous system. Neurons extend branches called dendrites and axons to form connections. Dscam helps ensure these branches grow and connect in an organized manner, preventing tangling or unnecessary overlap. This process, known as “self-avoidance,” allows a neuron’s own branches to recognize and repel each other.
In Drosophila melanogaster, Dscam mediates this self-avoidance, ensuring dendrites spread out without crossing. If Dscam function is lost in fruit flies, neurons show abnormal dendritic crossing and bundling. The expression of a single Dscam isoform in Drosophila neurons can restore self-avoidance, highlighting its role in this mechanism.
A Role in Immunity
Beyond its functions in the nervous system, Dscam also contributes to the innate immune system, particularly in insects and crustaceans. The vast diversity of Dscam variants allows the immune system to recognize and respond to a wide range of foreign invaders by generating pathogen-specific isoforms.
Dscam’s role in immunity involves phagocytosis, where immune cells, such as insect hemocytes, engulf and clear foreign particles like bacteria and fungi. Specific Dscam isoforms can bind to particular pathogens, facilitating their recognition and engulfment. For instance, research in the Chinese mitten crab shows that specific soluble Dscam isoforms bind to bacteria, enhancing their elimination by hemocytes through phagocytosis.
Implications for Human Health
The human gene, DSCAM, located on chromosome 21, is connected to Down syndrome, also known as Trisomy 21. Individuals with Down syndrome have an extra copy of chromosome 21, leading to overexpression of genes in that region, including DSCAM. This altered DSCAM dosage may contribute to the neurodevelopmental features of Down syndrome.
Research in mouse models of Down syndrome indicates that an extra copy of DSCAM can lead to increased axon growth and excess inhibitory neuronal connections in the cerebral cortex. These changes in synaptic development may contribute to the cognitive and intellectual differences in Down syndrome. DSCAM mutations or copy-number variations have also been linked to other human neurological conditions, such as autism spectrum disorders, bipolar disorder, and intellectual disability, highlighting its broader significance in brain development.