Neuropilin-1 and the Positions of Glomeruli in the Mouse Olfactory Bulb

Abstract

It is known since 1996 that mouse odorant receptors (ORs) are involved in determining the positions of the sites of coalescence of axons of olfactory sensory neurons (OSNs)—the thousands of glomeruli in the olfactory bulb. But the molecular and cellular mechanisms of OR-mediated axonal coalescence into glomeruli remain unclear. A model was proposed in 2006–2009 whereby OR-derived cAMP signals, rather than direct action of OR molecules, determine the target destinations (glomeruli) of OSNs in the bulb. This model hypothesizes that OR-derived cAMP signals determine the expression levels of neuropilin 1 (Nrp1) in OSN axon termini; that levels of Nrp1 in glomeruli form a gradient from anterior-low to posterior-high throughout the bulb; and that these Nrp1 levels mechanistically determine anterior-posterior patterning of glomeruli. Here, we describe the first independent evaluation of the Nrp1 model since it was formulated a decade ago. We tested the model for the well-characterized mouse OR M71 using our gene-targeted mouse strains, which are publicly available. In contradiction to the model, we observed a variety of configurations for the M71 glomeruli in the conditional Nrp1 knockout. We then reassessed the model for the original OR transgene with which the model was developed, using the same publicly available mouse strains. We discovered that glomerular positions do not undergo the simple anterior shift that has been reported in the conditional Nrp1 knockout for this OR transgene. Taken together, our findings do not support the Nrp1 model for the anterior-posterior patterning of glomerular positions in the olfactory bulb.

Activity-Dependent Gene Expression in the Mammalian Olfactory Epithelium

“…This model postulates that differing levels of cAMP signaling characteristic of each OR produce graded amounts of Nrp1, which helps determine the anterior-posterior positions of glomeruli (Imai et al 2006;Imai et al 2009). However, recent data reveal that Nrp1 levels in OSN axons in olfactory bulb glomeruli have a mosaic pattern rather than an anterior-posterior gradient as first reported, and that glomerular position in mice lacking Nrp1 is not shifted anteriorly as first reported (Zapiec et al 2016). These findings call into question whether activity-dependent expression of Nrp1 and its ligand Sema3A in OSNs contributes to determining the anterior-posterior positions of glomeruli.…”

Axonal Odorant Receptors Mediate Axon Targeting

“…See also Figure S8. location of olfactory glomeruli along the A-P axis, exhibits a global gradient along the A-P axis and a patchy distribution at the glomerular level (Assens et al, 2016;Col et al, 2007;Zapiec et al, 2016).…”

Primary sensory map formations reflect unique needs and molecular cues specific to each sensory system

“…Gradients of Nrp1 code for anterior-posterior patterning 53 in combination with matching expression of semaphorins 59– 61 . However, detailed tests question the proposed model of Nrp1 guidance by showing more complicated outcomes inconsistent with the simple Nrp1 gradient model 54 . Since G-coupled ORs are found on the growth cone of OSNs, those ORs could locally interact with the environment to guide confined responses via the cAMP/PKA intracellular signal cascades.…”