Signaling Mechanisms that Regulate Axon Guidance at the CNS Midline

University Of Pennsylvania, Philadelphia PA

Investigators

Abstract

In all bilaterally symmetric animals, the ability to coordinate the left and right sides of the body is critically important for sensory perception, motor behavior and cognitive function. The midline is an important organizing center for the development of nerve connections between the two sides of the body; many nerve cells grow connecting axons that cross over to the other side of the body through the midline only once, innervating targets on the opposite side of the body. The proposed research will enrich scientific understanding about the guidance molecules involved in this process, which are very similar between vertebrate and invertebrate animals, and work in the same ways. These experiments will also provide new and more detailed information about how signaling molecules modulate nerve fiber growth by changing the expression of genes that code for nerve fiber structural molecules. An integral component of the proposal will be to expand the high school outreach initiative established as a part of previous research. This expansion will include training and co-teaching with 15 Philadelphia public high school teachers, and is designed to increase high school scientific literacy and aptitude. The program is based on the researchers continuing collaboration with a handful of outstanding Philadelphia public high school teachers, who have worked in the investigator's laboratory over multiple summers. The focus is to develop simple experiments that can be performed with fruit flies and that illustrate key concepts in the formation and function of the nervous system, and at the same time, to raise awareness of the power of animal models for the study of biology. Determining the cell and molecular mechanisms that control the assembly of neural circuits is a central problem in developmental biology. Insights into these mechanisms promise to have important impacts on human health since many signaling molecules that contribute to wiring the nervous system are implicated in developmental disorders and cancer. In addition, understanding how axon growth and guidance are controlled during development may suggest strategies to promote neuronal regeneration after injury or disease. We propose to study the signaling mechanisms that promote axon attraction. The midline of the Drosophila embryonic CNS is an ideal system to dissect these signaling mechanisms. Like the vertebrate floor plate, the fly midline is an intermediate target for navigating axons, which must decide whether or not to cross. Netrin attracts commissural axons to the midline in both vertebrates and invertebrates through receptors of the Deleted in Colorectal Carcinoma (DCC) family (encoded by frazzled in the fly). However, it is unclear how Frazzled/DCC signaling leads to axon attraction and what additional mechanisms contribute to midline circuit assembly. We propose 1) to engage undergraduate researchers to continue an established genetic screen to identify new players in the regulation of midline axon guidance, 2) to conduct a genetic and biochemical characterization of roles of the Scar/WAVE complex and the microtubule binding protein Mars in Fra-mediated axon attraction and 3) to determine how the recently discovered role of Fra in activating gene transcription is spatially and temporally regulated by proteolytic cleavage of the Fra receptor. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.