Notch-Dependent Regulation of Netrin Pathway Controls Drosophila Transmedullary Neuron Axon Targeting and Optic Lobe Organization
60 Pages Posted: 24 Jan 2022 Publication Status: Review Complete
More...Abstract
During neural development, temporal and spatial patterning of neural progenitors as well as Notch-dependent binary fate choice between sister neurons contribute to the generation of neural diversity. How these upstream neural fate specification programs regulate downstream effector genes to control axon targeting and neuropil assembly remains less wellunderstood. Here we show that Notch-dependent binary fate choice in Drosophila medulla neurons regulates the expression of Netrin pathway components, which controls axon guidance of transmedullary (Tm) neurons and contributes to the assembly of optic lobe neuropils. We find Netrin signaling is required in two stages of Tm axon targeting. In the early stage, Netrin-B (NetB) is enriched throughout the lobula, where Tm axons target. Frazzled (Fra) is expressed broadly in medulla neurons and is required collectively in a group of early-born Tm neurons to establish the inner optic chiasm (IOC) through which Tm axons target lobula. Unc-5 is downregulated as Tm neurons undergo axon targeting, and misexpression of Unc-5 leads to their mistargeting to lobula plate. In the late stage, NetB is enriched in specific layers of lobula. Fra is required in the layer-specific targeting of Tm neurons that terminate in a NetB-enriched layer. Furthermore, we show that the enrichment of NetB in lobula requires its diffusibility and Fra receptors expressed in Tm neurons, while the presence of Unc-5 may negatively affect NetB enrichment. Finally, we show that NetB is expressed in the Notch-on hemilineage of medulla neurons, giving rise mostly to Tm and TmY neurons that target lobula. Loss of Notch signaling in Su(H) mutant clones abolishes NetB expression in the medulla and also results in upregulation of Unc-5 expression. Without medulla-originated NetB, Tm axons from late-born medulla columns cannot join the IOC and instead mistarget to lobula plate. Taken together, our results suggest that the coordinate repression of Unc-5 and activation of NetB by Notch signaling ensures neurons targeting lobula can capture and enrich NetB with their Fra receptors as well as secrete more NetB, forming a positive feedback mechanism that helps to distinguish lobula from lobula plate.
Keywords: axon guidance, Netrin pathway, Notch-dependent binary fate choice, Neural fate specification and neural circuit assembly, Drosophila optic lobe
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