JAX Scientists Discover Key Neurodevelopment Mutation
September 8, 2009
Professor Robert W. Burgess, Ph.D, has been a principal investigator at The Jackson Laboratory since 2001. His research program is designed primarily to understand the molecular mechanisms underlying the formation and maintenance of synaptic connections in the developing nervous system. One experimental model system used by the Burgess lab is the mouse retina, and recent studies have begun to illustrate the importance of cell adhesion molecules in neuronal circuit formation.
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Professor Burgess believes that DSCAM and related proteins are involved in many neurodevelopmental processes |
During normal neurodevelopment, many different cell types arise—for example, dopaminergic versus cholinergic neurons—that must be integrated into neuronal circuits. The functional circuitry of the vertebrate central nervous system is essentially a reiterated pattern of smaller columnar circuits. This is particularly clear in the retina, where rod and cone photoreceptors connect through a series of interneurons to retinal ganglion cells, the output neurons of the eye. These cells maintain a "retinotopic" projection of axons to the brain and thus, owing to the columnar circuitry, preserve a map of the visual world. To properly form these circuits, each neuron must form branched structures—dendritic arbors—of the proper size and shape to receive appropriate synaptic inputs. They must also be able to recognize neighboring cells of the same type (for example, other dopaminergic or other cholinergic neurons) and space their cell bodies appropriately to have the proper degree of overlap in the circuits, a process often called "tiling' or 'mosaic formation."
Recently, while screening mice for new mutations affecting neurodevelopment, the Burgess lab identified a mouse with a mutation in the gene encoding Down syndrome cell adhesion molecule (Dscam). The retinal cells that would normally express Dscam in this mouse fail to have normal dendritic arbors and regularly spaced cell bodies. Instead, cells of the same type clump together, and their dendrites form thick bundles. In this regard, the mouse Dscam gene functions like the Drosophila Dscam1 ortholog in a process termed "self-avoidance". However, one perplexing difference is that Drosophila Dscam1 undergoes extensive alternative splicing to generate tens of thousands of protein isoforms, each of which specifically binds other identical isoforms. In this way, it is clear how Drosophila Dscam1 allows many different cells each to sense "self." Vertebrate Dscams are not subject to appreciable alternative splicing, suggesting that at least some mechanistic differences from the fly exist.
The human DSCAM gene is named for its location on chromosome 21, in a region termed the "Down syndrome critical region" for its importance in Down syndrome (trisomy 21). The phenotype of the Dscam mutant mouse makes it clear that Dscam is critically involved in neurodevelopmental processes in the retina and other parts of the brain. Understanding the precise relationship between DSCAM and the neurodevelopmental abnormalities of Down syndrome will require additional experiments. However, the work in mice creates a model in which these studies can be done and demonstrates that the general principle of cell adhesion molecules conferring self-recognition and self-avoidance is conserved from Drosophila to mammals, raising the possibility that DSCAM, or related proteins, are central to many neurodevelopmental diseases.
References
(Authors in bold are Jackson Laboratory scientists.)
Fuerst PG, Koizumi A, Masland RH, Burgess RW. 2008. Neurite arborization and mosaic spacing in the mouse retina require DSCAM. Nature 451:470-4.
Fuerst PG and Burgess RW. 2009. Adhesion molecules in establishing retinal circuitry. Curr Opin Neurobiol Epub Aug. 4, 2009.
