Neuronal target recognition in Drosophila visual system

Specific patterns of neuronal connectivity arise in the developing nervous system as growing axons are first guided towards their target tissue, and then recognise their specific target cells within that tissue. While much progress has recently been made in elucidating the molecular mechanisms that guide axons towards their target region, the mechanisms by which individual axons recognise their specific targets remain largely unknown. The developing Drosophila visual system provides an ideal opportunity to investigate the process of target recognition. Each ommatidium of the Drosophila eye comprises 8 photoreceptor cells, R1-R8, that connect to targets in the optic lobe of the brain. The photoreceptors can be grouped into three classes, based on spectral sensitivity and target specificity. R1-R6 cells respond to visual light and connect to targets in a specific layer of the first optic ganglion, the lamina. R7 and R8 cells respond to ultraviolet and blue light respectively, and connect to targets in distinct layers of the second ganglion, the medulla. In an extensive loss-of-function genetic screen, we have identified 8 genes required specifically for R axon target recognition. In mutants for each of these 8 genes, R axons navigate correctly from the developing eye into the optic lobe, assuming their appropriate topographic locations, but connect to the wrong target cells. So far, the molecular nature of 5 of these genes has been determined. In this proposal, we plan to identify each of the 3 remaining genes, and to use molecular and genetic approaches to define further genes acting during R axon target recognition. Genetic and biochemical studies will examine the interactions between each of these genes and their products. This research will lead to a detailed understanding of the molecular mechanisms of target recognition in the Drosophila visual system. For axon guidance, conserved families of guidance molecules have been found to mediate analogous guidance decisions during development of the vertebrate and invertebrate nervous systems alike. We anticipate that a similar degree of conservation will be also found at the second step, target recongition. The molecular mechanisms that control target recognition in the Drosophila visual system should therefore also provide new insights into development of the vertebrate nervous system.

Our brains consist of trillions of nerve cells, called neurons, connected with each other in precise ways. These connections are determined in large part by genes that act during early development to guide nerve fibres towards their target regions, and then direct them to form connections with specific target cells. How trillions of neuronal connections can be specified by just a few thousand genes (at most) is one of the major mysteries in neuroscience and developmental biology. To try to understand how this process works, we have turned to a simple model system: the connection of retinal cells in the eye of the fruitfly Drosophila to specific target cells in the fly`s brain: a network that involves "just" a few hundred neurons. Using the genetic methods possible in Drosophila, we have been able to identify over 40 genes that direct the formation of these neuronal connections. Most of them have counterparts in our own genome, and it is likely that these genes have similar functions in the formation of some of the trillions of neuronal connections in our own brains. Mutations in the fly genes result in abnormal connections between the fly`s eye and its brain, and it is possible that mutations in the human counterparts of these genes may also underlie human developmental brain disorders. Moreover, knowing how neurons are connected up during development may one day help us to re-establish these connections following damage to the human central nervous system, for example following spinal cord injury or stroke. Our discoveries of the developmental mechanisms that specify neuronal connections in the fly`s brain is a modest but important first step towards these goals.