Proper circuit assembly is critical to the creation of a healthy nervous system. Understanding the molecular and genetic mechanisms by which neurons form circuits will permit a more complete understanding of the development of the nervous system in normal and in disease conditions. This research proposal aims to study the molecular mechanisms controlling the formation of functional neural circuits in Drosophila. I have shown that proper dendrite patterning in multidendritic (md) sensory neurons in the Drosophila PNS requires the Down syndrome cell adhesion molecule (Dscam). I propose three specific aims to further understand the mechanisms of neural patterning, and particularly, the role of Dscam diversity and signaling in recognition specificity and circuit formation. 1: The Dscam locus encodes over 38,000 distinct isoforms through alternative splicing. Individual isoforms engage in homophilic interactions that allow dendrites to selectively recognize and interact with branches from the same cell. I hypothesize that the discrimination of self vs. non-self relies on a quantitative comparison of Dscam isoform similarity. Precise genetic manipulations of Dscam isoform expression will reveal how Dscam specifies neuron identity. 2: Preliminary results show that increasing expression of a single Dscam isoform within a small set of neurons disrupts the neural circuitry underlying stereotyped post-eclosion behaviors. I hypothesize that Dscam diversity is required for proper cell-cell interactions leading to the formation or maintenance of the circuitry underlying this behavior. I will use this system to ask how Dscam functions during circuit assembly. 3:1 have accumulated evidence that Dscam-mediated repulsion requires signaling through its cytoplasmic tail; however, little is known about the downstream molecules involved in Dscam signaling. Taking advantage of the dramatic effect of Dscam overexpression on a easily screened, stereotyped behavior, I propose to conduct a suppressor screen to identify genes involved in Dscam signaling and neural patterning. This research is relevant to our greater understanding of how single genes and molecules give rise to the exquisitely precise connectivity observed in the brain. By understanding the complex signaling that underlies the formation of complex circuits from individual neurons, we will be better positioned to understand and ultimately treat disease effecting neural development and degeneration. ? ?
| Matthews, Benjamin J; Grueber, Wesley B (2011) Dscam1-mediated self-avoidance counters netrin-dependent targeting of dendrites in Drosophila. Curr Biol 21:1480-7 |
| Corty, Megan M; Matthews, Benjamin J; Grueber, Wesley B (2009) Molecules and mechanisms of dendrite development in Drosophila. Development 136:1049-61 |
| Hattori, Daisuke; Chen, Yi; Matthews, Benjamin J et al. (2009) Robust discrimination between self and non-self neurites requires thousands of Dscam1 isoforms. Nature 461:644-8 |
