Shh‐proteoglycan interactions regulate maturation of olfactory glomerular circuitry

Abstract

The olfactory system relies on precise circuitry connecting olfactory sensory neurons (OSNs) and appropriate relay and processing neurons of the olfactory bulb (OB). In mammals, the exact correspondence between specific olfactory receptor types and individual glomeruli enables a spatially precise map of glomerular activation that corresponds to distinct odors. However, the mechanisms that govern the establishment and maintenance of the glomerular circuitry are largely unknown. Here we show that high levels of Sonic Hedgehog (Shh) signaling at multiple sites enable refinement and maintenance of olfactory glomerular circuitry. Mice expressing a mutant version of Shh (ShhAla/Ala), with impaired binding to proteoglycan co-receptors, exhibit disproportionately small olfactory bulbs containing fewer glomeruli. Notably, in mutant animals the correspondence between individual glomeruli and specific olfactory receptors is lost, as olfactory sensory neurons expressing different olfactory receptors converge on the same glomeruli. These deficits arise at late stages in post-natal development and continue into adulthood, indicating impaired pruning of erroneous connections within the olfactory bulb. In addition, mature ShhAla/Ala mice exhibit decreased proliferation in the subventricular zone (SVZ), with particular reduction in neurogenesis of calbindin-expressing periglomerular cells. Thus, Shh interactions with proteoglycan co-receptors function at multiple locations to regulate neurogenesis and precise olfactory connectivity, thereby promoting functional neuronal circuitry.

Hedgehog signaling regulates ciliary localization of mouse odorant receptors

“…The localization in target neurons is in line with the findings that Shh influences OSN axon growth and branching (11). Intriguingly, a low Shh level in human nasal mucus has been associated with reduced sense of smell (hyposmia) (8,9).…”

The role of a ciliary GTPase in the regulation of neuronal maturation of olfactory sensory neurons

“…These findings suggest that the HH signaling pathway is not involved in the ARL13B-mediated maturation of OSNs. We cannot definitively exclude the possibility of an ARL13B-HH mechanism during development given that the role of HH in the olfactory system has been reported during embryogenesis ( Balmer and LaMantia, 2004 ; Gong et al, 2009 ; Persson et al, 2014 ), a time at which we did not assay HH activity. However, given that the 123-Arl13b phenotype exacerbates with age and that HH activity dramatically declines by 1 month of age we find this possibility unlikely.…”

Adult Neurogenesis and Gliogenesis: Possible Mechanisms for Neurorestoration

“…In the adult rodent brain, neuronal progenitor cells generated in the SVZ travel through the rostral migration stream and settle down in the olfactory bulb, where they differentiate into local interneurons, granule cells, and periglomerular cells [ 40 , 41 , 42 , 43 , 44 ]. Adult neurogenesis in the rodent olfactory bulb is required for specific forms of olfactory behavior, and certain genetic manipulations result in conditional and selective enhancement of olfactory neurogenesis [ 45 , 46 ]. In addition, gliogenesis has been found in the rodent olfactory bulb and the SVZ of multiple sclerosis patients [ 7 , 47 ].…”