Building the topographic map in the mammalian olfactory bulb is explained by a model based on two axes along which sensory neurons are guided: one dorsoventral and one anteroposterior. This latter axis relies on specific expression levels of Nrp1. To evaluate the role of this receptor in this process, we used an in vivo genetic approach to decrease or suppress Nrp1 in specific neuronal populations and at different time points during axonal targeting. We observed, in neurons that express the M71 or M72 odorant receptors, that Nrp1 inactivation leads to two distinct wiring alterations, depending on the time at which Nrp1 expression is altered: first, a surprising dorsal shift of the M71 and M72 glomeruli, which often fuse with their contralateral counterparts, and second the formation of anteriorized glomeruli. The two phenotypes are partly recapitulated in mice lacking the Nrp1 ligand Sema3A and in mice whose sensory neurons express an Nrp1 mutant unable to bind Sema3A. Using a mosaic conditional approach, we show that M71 axonal fibers can bypass the Nrp1 signals that define their target area, since they are hijacked and coalesce with Nrp1-deficient M71-expressing axons that target elsewhere. Together, these findings show drastically different axonal targeting outcomes dependent on the timing at which Nrp1/Sema3A signaling is altered.
The authors declare no competing or financial interests.
A.A., J.A.D.C., A.N., C.K. and P.F. carried out experimental studies. A.A., J.A.D.C., A.N., Q.D., C.K., P.F., A.C. and I.R. performed data analyses. I.R. and A.C. conceived the study. I.R. wrote the bulk of the manuscript. All authors discussed the results and commented on the manuscript.
This work was supported by grants from the Swiss National Science Foundation [Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung; 31003A_149753 and 310030E-135910 to I.R., CR33I13_143723 to I.R. and A.C., and 31003A_153410 to A.C.]; and from the Research Centers in Minority Institutions Program Grant from the National Institute on Minority Health and Health Disparities [MD007599 to P.F.]; and the National Institutes of Health [SC1 GM088114 to P.F.]. Deposited in PMC for release after 12 months.
Supplementary information available online at http://dev.biologists.org/lookup/doi/10.1242/dev.138941.supplemental
- Received April 25, 2016.
- Accepted August 23, 2016.