Visual information detected by the retina is sent for further processing to deeper layers of the visual centers that feed into specialized behavior circuits. Much is known about how visual centers and local circuits function, but we do not understand how the many cell types that compose them are generated and how these circuits assemble and are coordinated between brain regions. We study the simplified, yet highly performing visual system of Drosophila for which we have obtained a deep understanding of neural diversity, mechanisms that also apply to mammalian neurogenesis. In a separately funded grant, we have generated a very large dataset where we have identified through single cell mRNA sequencing the individual transcriptome of most (169 neural types) neurons and glia in the four optic lobe ganglia, lamina, medulla, lobula and lobula plate, through six development stages starting when the neurons are first generated. This represents a huge resource that will allow us to identify the molecular pathways involved in the processes studied here. In the current proposal, we will define how the circuits formed by optic lobe neurons are assembled and how development of the different optic lobe neuropils is synchronized:
Aim 1. Retinotopic projection of photoreceptors to the lamina and medulla. We will define the role of the lamina in the establishment of retinotopy in the medulla and what guides photoreceptors and lamina neurons to their retinotopic location. We will then identify the molecular guidance pathways involved in pathfinding in lamina and medulla, and determine the potential role of pioneer neurons that might guide retinotopy of the other neurons.
Aim 2 Timing of differentiation and layer formation in the medulla neuropil. Medulla neurons are born from the same neural progenitors in a sequential order, a fundamental mechanism of 'temporal patterning'. We will test the model that temporal patterning allows medulla neurons to progressively innervate each layer of the lobula and of the medulla and we will define the molecular mechanisms synchronizing birth order and layer formation.
Aim 3 : Development of output neurons from the lobula: Visual features and optic glomeruli. Signals from the medulla are conveyed to the lobula and are then passed on to Lobula Columnar Neurons (LCNs) that connect to 'optic glomeruli' that control behavior. We will study how ~20 subtypes of LCNs connect to different layers of the lobula and to specific glomeruli in the central brain and will define the molecular mechanisms of their specific targeting.
Aim 4. Building the broad-field motion pathway. Motion is computed by neurons that compare the outputs of upstream neurons in a specific orientation. We will investigate the developmental programs that instruct the dendrite orientation of the first orientation-selective neurons (T4 and T5) and how they each project to one of the 4 layers of the lobula plate that each detects motion in one of 4 cardinal directions. This study will provide fundamental insights into the coordination of various elements of a simple and amenable visual system. Our findings will not only provide novel fundamental concepts for the development of circuits for sensory processing, but will also contribute general concepts applicable to circuit formation in vertebrates.

Public Health Relevance

Drosophila, with its genetic amenability and simple visual system, yet very sophisticated visual performances, is a very powerful model system to study how the visual system is built during development. Using the results of single cell mRNA sequencing, we investigate the mechanisms controlling specific connections among optic lobe neurons and how the formation of the different layers of visual processing is coordinated. The principles deduced from this project will be applicable to other sensory systems such as the mammalian retina.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
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Greenwell, Thomas
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New York University
Schools of Arts and Sciences
New York
United States
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Holguera, Isabel; Desplan, Claude (2018) Neuronal specification in space and time. Science 362:176-180
Minkina, Olga; Desplan, Claude (2018) Large-Scale CRISPR-Mediated Somatic Mutagenesis Identifies a Signaling Pathway that Guides Retinal Development. Neuron 98:1-3
Rossi, Anthony M; Fernandes, Vilaiwan M; Desplan, Claude (2017) Timing temporal transitions during brain development. Curr Opin Neurobiol 42:84-92
Rossi, Anthony M; Desplan, Claude (2017) Asymmetric Notch Amplification to Secure Stem Cell Identity. Dev Cell 40:513-514
Wells, Brent S; Pistillo, Daniela; Barnhart, Erin et al. (2017) Parallel Activin and BMP signaling coordinates R7/R8 photoreceptor subtype pairing in the stochastic Drosophila retina. Elife 6:
Fernandes, Vilaiwan M; Chen, Zhenqing; Rossi, Anthony M et al. (2017) Glia relay differentiation cues to coordinate neuronal development in Drosophila. Science 357:886-891
Perry, Michael; Konstantinides, Nikos; Pinto-Teixeira, Filipe et al. (2017) Generation and Evolution of Neural Cell Types and Circuits: Insights from the Drosophila Visual System. Annu Rev Genet 51:501-527
Chen, Zhenqing; Del Valle Rodriguez, Alberto; Li, Xin et al. (2016) A Unique Class of Neural Progenitors in the Drosophila Optic Lobe Generates Both Migrating Neurons and Glia. Cell Rep 15:774-786
Pinto-Teixeira, Filipe; Konstantinides, Nikolaos; Desplan, Claude (2016) Programmed cell death acts at different stages of Drosophila neurodevelopment to shape the central nervous system. FEBS Lett 590:2435-2453
Courgeon, Maximilien; Konstantinides, Nikolaos; Desplan, Claude (2015) Cell competition: dying for communal interest. Curr Biol 25:R339-41

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