title: 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 (Shh(Ala/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 Shh(Ala/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.
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts; Department of Neurobiology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Laura
authors.initials: L
authors.lastname: Persson
authors.forename: Rochelle M
authors.initials: RM
authors.lastname: Witt
authors.forename: Meghan
authors.initials: M
authors.lastname: Galligan
authors.forename: Paul L
authors.initials: PL
authors.lastname: Greer
authors.forename: Adriana
authors.initials: A
authors.lastname: Eisner
authors.forename: Maria F
authors.initials: MF
authors.lastname: Pazyra-Murphy
authors.forename: Sandeep R
authors.initials: SR
authors.lastname: Datta
authors.forename: Rosalind A
authors.initials: RA
authors.lastname: Segal
mesh_terms: D000818:Animals; D064026:Calbindins / Q000378:metabolism; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008822:Mice, Transgenic; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism; D055495:Neurogenesis / Q000502:physiology; D009474:Neurons / Q000473:pathology / Q000502:physiology; D009830:Olfactory Bulb / Q000254:growth & development* / Q000473:pathology / Q000503:physiopathology; D051842:Olfactory Marker Protein / Q000378:metabolism; D009833:Olfactory Pathways / Q000254:growth & development* / Q000473:pathology / Q000503:physiopathology; D009929:Organ Size; D011509:Proteoglycans / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D064026:Calbindins; D053823:Hedgehog Proteins; D019006:Neural Cell Adhesion Molecules; D051842:Olfactory Marker Protein; C497598:Omp protein, mouse; D011509:Proteoglycans; D012333:RNA, Messenger; C465570:Shh protein, mouse
keywords: Shh; axon pruning; calbindin; glomeruli; olfactory bulb; proteoglycan