Molecular genetics of axon guidance in Drosophila melanogaster

Abstract

Listen

Translate article

Understanding the cellular and molecular mechanisms governing axon guidance and synaptogenesis is a central issue in developmental neurobiology. The Drosophila embryonic central nervous system, with its simplicity and genetic accessibility, is an ideal model system to examine these problems. One signaling mechanism by which growth cones respond to guidance factors is the control of tyrosine phosphorylation. Genetic studies in Drosophila have shown that neural receptor protein tyrosine phosphatases (RPTPs) are important regulators of motor axon guidance decisions. Chapters 2 and 3 of this thesis describe genetic studies of the RPTP gene DPTP10D. Removing DPTP1OD and DPTP69D causes axon pathfinding errors at the midline and within the longitudinal tracts. These RPTPs genetically interact with genes involved in repulsion from the midline, including Slit, Roundabout and Commissureless. Slit is a midline repulsive signal, while Roundabout is the receptor for Slit. The phosphatases are likely to be components of signaling pathways downstream of Roundabout. DPTP10D is also involved in growth cone guidance decisions in the embryonic neuromuscular system. Phenotypic analyses of RPTP mutant combinations show that DPTPlOD works together with other RPTPs to promote bifurcation of the SNa nerve and allow the ISNb nerve to separate from the common ISN pathway. DPTPlOD, however, has a competitive relationship with the other RPTPs in controlling growth of the ISM These results show that the functional relationships among the four neural RPTPs are complex. At individual choice points, RPTPs can have cooperative, collaborative, or antagonistic functions in controlling guidance. In Chapter 4, I describe an overexpression/misexpression P element screen for new genes involved in axon guidance. This screen allows identification and rapid cloning of genes that cause axon guidance defects when they are overexpressed in all neurons or all muscle fibers. One known axon guidance gene and several novel genes have already been identified in this screen, indicating that it may provide a powerful method to identify new genes that regulate axon guidance and synaptogenesis. There are also three Appendices in the thesis. Two of these are reviews that I coauthored. The third Appendix describes a genetic analysis of the RPTP substrate protein gp150.