Neural map formation in the mouse olfactory system

Abstract

In the mouse olfactory system, odorants are detected by ~1,000 different odorant receptors (ORs) produced by olfactory sensory neurons (OSNs). Each OSN expresses only one functional OR species, which is referred to as the "one neuron-one receptor" rule. Furthermore, OSN axons bearing the same OR converge to a specific projection site in the olfactory bulb (OB) forming a glomerular structure, i.e., the "one glomerulus-one receptor" rule. Based on these basic rules, binding signals of odorants detected by OSNs are converted to topographic information of activated glomeruli in the OB. During development, the glomerular map is formed by the combination of two genetically programmed processes: one is OR-independent projection along the dorsal-ventral axis, and the other is OR-dependent projection along the anterior-posterior axis. The map is further refined in an activity-dependent manner during the neonatal period. Here, we summarize recent progress of neural map formation in the mouse olfactory system.

Fig. 1

The mouse olfactory system. a MOR28-expressing OSN axons are shown in blue stained with X-gal in the transgenic mouse containing MOR28-ires-tau-lacZ. OSNs expressing the MOR28 transgene converge their axons to a specific glomerulus in the OB (indicated by an arrow). b In the OE, each OSN expresses only one functional OR gene in a monoallelic manner. Furthermore, OSN axons expressing the same OR species target to a specific site in the OB, forming a glomerular structure. c Odor signals received in the OE are converted to a topographic map of activated glomeruli in the OB. OE olfactory epithelium, OB olfactory bulb, D dorsal, V ventral, A anterior, P posterior

Fig. 2

Stepwise regulation of olfactory map formation. a OSN axons are guided to approximate destinations in the OB by a combination of D–V patterning and A–P patterning. D–V projection is regulated by the anatomical locations of OSNs within the OE. A–P projection is achieved through cAMP signals induced by agonist-independent OR activities. These processes, forming a coarse map topography, are genetically programmed and independent of the neuronal-activity of OSNs. b During the neonatal period, the map is further refined in an activity-dependent manner. Glomerular segregation occurs via adhesive and repulsive interactions of neighboring axons. DM dorsomedial, VL ventrolateral, D dorsal, V ventral, A anterior, P posterior, OE olfactory epithelium, OB olfactory bulb

Fig. 3

A model for axonal projection of OSNs along the D–V axis. In the OE, D-zone OSNs mature first and extend their axons to the OB earlier than V-zone OSNs. Early arriving D-zone axons express Robo2 and project to the prospective anterodorsal domain of the OB with the aid of repulsive interactions with Slit1 expressed in the septum and ventral OB at early developmental stages (left). In OSNs, an axon guidance receptor, Nrp2, and its repulsive ligand, Sema3F, are expressed in a complementary and graded manner. Sema3F is secreted in the anterodorsal region of the OB by early arriving D-zone axons (middle). Axonal extension of OSNs occurs sequentially along the DM–VL axis of the OE as the OB grows ventrally during embryonic development. This sequential projection helps to maintain topographic order during the process of axonal projection. Sema3F secreted by the D-zone axons in the OB prevents the late-arriving Nrp2⁺ axons from invading the dorsal region of the OB (right). DM dorsomedial, VL ventrolateral, D dorsal, V ventral, A anterior, P posterior, ED embryonic day

Fig. 4

a Conformational changes of GPCRs (modified from Ref. [39] by Rasmussen et al.). G-protein-coupled receptors (GPCRs) are known to possess two different conformations, active and inactive. In the absence of ligands, GPCRs spontaneously interchange between these conformations, generating agonist-independent baseline activity (right). b Each OR possesses a unique level of baseline activity and generates a specific amount of cAMP using G_s, but not G_olf. The levels of cAMP signals are converted to transcription levels of A–P targeting molecules, e.g., Nrp1 and PlxnA1. Activity-high axons project to the posterior region of the OB, whereas activity-low axons project to the anterior OB. TM transmembrane domain, OR odorant receptor

Fig. 5

A two-step model for OR-instructed axonal projection of OSNs. OR-instructed A–P targeting and glomerular segregation are differentially regulated by distinct OR-derived cAMP signals. a A–P targeting is regulated by agonist-independent OR activity using a non-canonical signaling pathway. In immature OSNs, each OR generates a unique level of cAMP by agonist-independent baseline activity via G_s and ACIII. The level of cAMP signals is converted to transcription level of A–P targeting molecules, e.g., Nrp1 and PlxnA1, through the cAMP-activated PKA pathway, phosphorylating the transcription factor CREB. b Glomerular segregation is regulated by stimulus-driven neuronal activity using a canonical signal transduction pathway. In mature OSNs, different ORs generate different levels of neuronal activity using extrinsic stimuli, which ultimately determine the transcription levels of glomerular segregation molecules, e.g., Kirrel2 and Kirrel3. OR odorant receptor, AC adenylyl cyclase, PKA protein kinase A, CREB cAMP responsive element binding protein, PDE phosphodiesterase