To elucidate the mechanisms that control the formation of neuronal connections in the visual system, it is pivotal to understand how neurons and glial cells are generated as the starting point of circuit formation. These insights are also instrumental for designing genetic approaches that enable cell type-specific genetic manipulations for connectivity studies.
To uncover determinants that are required for target neuron development in the optic lobe, we have conducted a forward genetic mosaic screen. This project led us to investigate the modes of neurogenesis in higher visual information processing centers. In the fly visual system, neurons in the four ganglia arise from two neuroepithelia, the outer and inner proliferation centers (OPC and IPC). The OPC primarily generates neurons for the lamina and medulla, and the IPC for the lobula plate and lobula. Typically neuroblasts, the neural stem cell equivalents in flies, arise by delamination or conversion from neuroepithelial cells. Neuroblasts divide asymmetrically to self-renew and produce a ganglion mother cell, which in turn divides to generate neurons and/or glia.
However, a region of the IPC uses a different strategy to produce its neurons. Neuroepithelial cells progressively convert into a distinct progenitor type. These progenitors migrate within cell streams to a second domain, where they mature into proliferating neuroblasts.
Our studies revealed that migratory progenitors emerge by a mechanism similar to epithelial-mesenchymal transition (EMT), although entirely taking place in the brain. This process requires the function of the Snail transcription factor Escargot. Moreover, we uncovered several transcription factors essential for regulating the supply rate and maturation of neuroblasts. Their sequential and cross-regulatory interactions enable neuroblasts to produce two neuron populations by switching competence.
In the third instar larval optic lobe of Drosophila, neurogenesis and gliogenesis are tightly linked with initial R-cell projection pattern formation. R1-R6 axons terminate between rows of glia in the lamina. We previously demonstrated that glia act as intermediate targets required to stop R1-R6 axons in the lamina. The transcription factors Glial cells missing (Gcm) and Gcm2 promote glial fate acquisition in the Drosophila embryo. We found a redundant function for these determinants in gliogenesis in the postembryonic optic lobe, and further confirmed the role of glia in controlling R1-R6 axon targeting. Unexpectedly, Gcm and Gcm2 also mediate neuronal development upstream of the transcription factor Dachshund and in collaboration with the Hedgehog signaling pathway.
Glial cells continue to be closely associated with neurons in the pupal and adult visual system. They develop highly elaborate, yet stereotypic branches. However, the molecular mechanisms that control the morphogenesis of their processes and their interactions with neurons are poorly understood. We therefore focus on one glial cell type, the medulla neuropil glia because of their striking shape. Ongoing research in our laboratory seeks to identify membrane-bound and secreted determinants that (1) regulate glial branch formation and (2) influence the formation of neuronal arborizations and synaptic contacts during metamorphosis.