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The Drosophila mushroom body (MB) is composed of parallel axonal fibers from intrinsic Kenyon cells (KCs). The parallel fibers are bundled into five MB lobes innervated by extrinsic neurons, including dopaminergic neurons (DANs) and MB output neurons (MBONs) that project axons or dendrites to the MB lobes, respectively. Each DAN and MBON innervates specific regions in the lobes and collectively subdivides them into 15 zones. How such modular circuit architecture is established remains unknown. Here, we followed the development of the DANs and MBONs targeting the vertical lobes of the adult MB. We found that these extrinsic neurons innervate the lobes sequentially and their neurite arborizations in the MB lobe zones are independent of each other. Ablation of DAN axons or MBON dendrites in a zone had a minimal effect on other extrinsic neurites in the same or neighboring zones, suggesting that these neurons do not use tiling mechanisms to establish zonal borders. In contrast, KC axons are necessary for the development of extrinsic neurites. Dendrites of some vertical lobeinnervating MBONs were redirected to specific zones in the horizontal lobes when their normal target lobes were missing, indicating a hierarchical organization of guidance signals for the MBON dendrites. We show that Semaphorin 1a is required in MBONs to innervate three specific MB zones, and overexpression of semaphorin 1a is sufficient to redirect DAN dendrites to these zones. Our study provides an initial characterization of the cellular and molecular mechanisms underlying the assembly process of MB extrinsic neurons. [ABSTRACT FROM AUTHOR]

Intrinsic mechanisms such as temporal series of transcription factors orchestrate neurogenesis from a limited number of neural progenitors in the brain. Extrinsic regulations, however, remain largely unexplored. Here we describe a two-step glia-derived signal that regulates neurogenesis in the Drosophila mushroom body (MB). In a temporal manner, glial-specific ubiquitin ligase dSmurf activates non-cell-autonomous Hedgehog signaling propagation by targeting the receptor Patched to suppress and promote the exit of MB neuroblast (NB) proliferation, thereby specifying the correct α/β cell number without affecting differentiation. Independent of NB proliferation, dSmurf also stabilizes the expression of the cell-adhesion molecule Fasciclin II (FasII) via its WW domains and regulates FasII homophilic interaction between glia and MB axons to refine α/β-lobe integrity. Our findings provide insights into how extrinsic glia-to-neuron communication coordinates with NB proliferation capacity to regulate MB neurogenesis; glial proteostasis is likely a generalized mechanism in orchestrating neurogenesis. [ABSTRACT FROM AUTHOR]