Degenerating Neurons Direct the Circuit

Science Signaling  13 Dec 2011:
Vol. 4, Issue 203, pp. ec345
DOI: 10.1126/scisignal.4203ec345

Brain development involves a complex interplay of cell growth, death, and migration and synapse formation. Sweeney et al. used the Drosophila olfactory circuit to study signals that direct axons to the proper site in the developing antennal lobe. Development of the olfactory circuit occurs in two phases—an early phase in which projection neurons (PNs) migrate independently of the adult olfactory receptor neurons (ORNs) and a later phase in which the ORN axons and PN dendrites interact with each other. In the early phase, larval ORNs degenerate, allowing the embryonic PN dendrites to remodel. Semaphorin-1a (Sema-1a) is a transmembrane protein present in a graded distribution on PNs that instructs PN dendrites to migrate along the dorsolateral-ventromedial axis, such that PNs with high Sema-1 project to the dorsolateral antennal lobe and those with low Sema-1a project to the ventromedial lobe. Although Sema family proteins typically interact with plexins, Sweeney et al. used a soluble fusion protein of Sema-1a to show that this protein bound to cells heterologously expressing a form of Sema-2a engineered to be membrane-tethered (Sema-2a and Sema-2b are naturally secreted proteins). Before the arrival of adult ORNs in the antennal lobe, Sema-2a and Sema-2b were enriched medially and vetromedially, which is the opposite pattern observed for Sema-1a. Flies lacking Sema-2a and Sema-2b (either genetically or through targeted knockdown) exhibited inappropriate ventromedial targeting of PNs in the antennal lobe, whereas deficiency in plexinA or plexinB failed to impair PN targeting. Targeted knockdown experiments showed that PNs and ORNs were a source of Sema-2a. Cellular ablation experiments with larval ORNs and targeted knockdown experiments indicated that Sema-2a and Sema-2b produced by larval ORN were important for proper dorsolateral targeting of the PNs. Thus, the authors propose that the degenerating larval ORNs produce Sema-2a and Sema-2b, which directs the PNs to form appropriate dendritic connections in the developing adult olfactory system.

L. B. Sweeney, Y.-H. Chou, Z. Wu, W. Joo, T. Komiyama, C. J. Potter, A. L. Kolodkin, K. C. Garcia, L. Luo, Secreted semaphorins from degenerating larval ORN axons direct adult projection neuron dendrite targeting. Neuron 72, 734–747 (2011). [Online Journal]