Mechanisms of neural patterning and the generation of neural diversity in the brain

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Project Summary To investigate the generation of neural diversity, we use the simple brain of Drosophila that has only 100,000 neurons but can support complex behaviors and simple learning. The highly deterministic nature of Drosophila brain development allows us to define general rules that control the generation of neural diversity and are applicable to mammalian development, even when this is further modulated by activity-dependent plasticity. The genetic control of optic lobe development can be investigated in depth thanks to the repetitive nature of the system, where information from the 800 unit-eyes (ommatidia) projects to 800 parallel retinotopic columns that sequentially process the visual information through more than 200 cell types. The generation of neural diversity results from the integration of three mechanisms: (i) ~800 medulla neuroblasts (NBs) are patterned by the sequential expression of temporal transcription factors that generate distinct types of neurons at each temporal window. (ii) NBs produce different neurons depending on their location in the neuroepithelium: Spatial factors locally modify the outcome of the temporal series. (iii) Binary fate choice via Notch signaling further diversifies the two daughters of ganglion mother cells (GMCs) born from each NB division. In contrast, NB transitions in the mushroom body, a brain region involved in learning, are controlled by extrinsic factors, generating fewer neuron types through the use of extremely long lineages. The broad context of this proposal will address how basic principles of neurogenesis explain the vast diversity of neurons in the optic lobes and the restricted diversity in the mushroom body, and will help us understand more complex brain structures and instruct further studies in mammals. We will investigate the mechanisms controlling neurogenesis through 4 aims: Aim 1: Temporal progression of neuroblasts: Timing and transition mechanisms: Temporal patterning is a general mechanism to generate neural diversity in flies and vertebrates. We will identify all the temporal factors and investigate their mode of cross-regulation that controls the timing of transitions. Aim 2. Intrinsic specification of neuroblasts in culture: A given temporal transcription factor appears to control the expression of the next factor in the series and to repress the previous factor to form a transcriptional clock mechanism. We will use live imaging of transcription (MS2 system) and of protein expression in vivo and in cultured NBs to investigate the intrinsic molecular mechanisms controlling the timing of transitions. Aim 3. Specification of multi-columnar neurons: We will investigate how multicolumnar neurons are produced locally in response to spatial factors while innervating the entire retinotopic map. We will also investigate how their cell bodies move to distribute throughout the optic lobe. Aim 4. Extrinsic cues for neuroblast transitions in the mushroom body: The mushroom body NBs have very long lineages but produce a limited number of cell types. We will study how Ecdysone and Activin signaling mediate extrinsic transitions between cell types and how they control gradients of RNA binding proteins acting in neuroblasts.