Abstract
Mushroom body (MB) is a prominent structure essential for olfactory learning and memory in the Drosophila brain. The development of the MB involves the appropriate guidance of axon lobes and sister axon branches. Appropriate guidance that accurately shapes MB development requires the integration of various guidance cues provided by a series of cell types, which guide axons to reach their final positions within the MB neuropils. Netrins are axonal guidance molecules that are conserved regulators of embryonic nerve cord patterning. However, whether they contribute to MB morphogenesis has not yet been evaluated. Here, we find that Netrin-B (NetB) is highly expressed in the MB lobes, regulating lobe length through genetic interactions with the receptors Frazzled and Uncoordinated-5 from 24 h after pupal formation onwards. We observe that overexpression of NetB causes severe β lobe fusion in the MB, which is similar to the MB defects seen in the Drosophila model of fragile X syndrome (FXS). Our results further show that fragile-X mental retardation protein FMRP inhibits the translational activity of human ortholog Netrin-1 (NTN1). Knock-down of NetB significantly rescues the MB defects and ameliorates deficits in the learning and memory in FXS model Drosophila. These results indicate a critical role for NetB in MB lobe extension and identify NetB as a novel target of FMRP which contributes to learning and memory.
Highlights
To form a complete and functional nervous system, neurons need to extend axons to reach specific targets
Drosophila NetB regulates Mushroom body (MB) lobe extension To investigate the roles of Drosophila netrins in MB development, we assessed the overall structure of the adult MB in wild type (WT), NetA deletion mutant NetAΔ, and NetB deletion mutant NetBΔ flies
Two Drosophila homologs of Netrin have been identified and share high homology, we demonstrate that NetB, but not NetA, regulates axon lobe extension of MB neurons
Summary
To form a complete and functional nervous system, neurons need to extend axons to reach specific targets. As key axonal guidance molecules, detailed studies have been conducted to investigate their roles in ventral nerve cord (VNC) development. Both NetA and NetB are highly expressed by the cells of the VNC midline, mainly guiding commissural axons either toward or away from the midline. In Drosophila, Frazzled (Fra), Uncoordinated-5 (Unc-5) and Down syndrome cell adhesion molecule (Dscam) have been identified as the three main receptors of netrins. Dscam serves as an attractive receptor which acts in parallel with Fra during VNC development, but it can respond to multiple other as-yet-unidentified ligands [11,12,13,14]. During MB development, Dscam is required for MB axon sister branch segregation [15,16,17], but it is less clear whether Fra and Unc-5 regulate MB development
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