title: Loss of Gli3 and Shh function disrupts olfactory axon trajectories.
abstract: The transcriptional regulator Gli3 and the secreted signal Shh influence induction, patterning, and differentiation at several sites of mesenchymal/epithelial (M/E) interaction including the limbs, heart, face, and forebrain. We asked whether loss of function of these two genes has specific consequences for early differentiation of the primary olfactory pathway-which comprises both craniofacial and forebrain structures and depends on M/E induction during initial stages of development. Loss of Gli3 or Shh function does not compromise several aspects of olfactory receptor neuron (ORN) and olfactory ensheathing cell maturation; however, directed outgrowth of ORN axons and their initial targeting to the telencephalon is altered. In Gli3 mutant extra toes-Jackson (Xt(J)Xt(J)) embryos, ORN axons defasciculate and project aberrantly near the forebrain. They rarely enter the central nervous system, and their association with mesenchymal laminin is disrupted. In Shh-/-embryos, ORN axons exit a single olfactory epithelium (OE) that develops centrally within an altered mesenchymal environment in a dysmorphic proboscis. These axons project as a single nerve toward the mutant forebrain; however, their trajectory varies according to the position of the proboscis relative to the forebrain. These alterations in axon outgrowth probably reflect compromised inductive interactions in the olfactory primordia because neither Gli3 nor Shh are expressed in olfactory neurons. Thus, two genes that influence induction and subsequent differentiation of craniofacial structures and the forebrain have distinct consequences for ORN axon growth during the initial genesis of the olfactory pathway.
authors.affiliation: Department of Cell & Molecular Physiology, Curriculum in Neurobiology and University of North Carolina Neuroscience Center, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, North Carolina 27599, USA.
authors.forename: Curtis William
authors.initials: CW
authors.lastname: Balmer
authors.forename: Anthony-Samuel
authors.initials: AS
authors.lastname: LaMantia
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001369:Axons / Q000502:physiology*; D001425:Bacterial Outer Membrane Proteins / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins; D006690:Bisbenzimidazole / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D004622:Embryo, Mammalian; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D019922:GAP-43 Protein / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D051741:Kruppel-Like Transcription Factors; D007797:Laminin / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009297:Nasal Mucosa / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism; D009831:Olfactory Mucosa / Q000166:cytology*; D018034:Olfactory Receptor Neurons / Q000378:metabolism* / Q000502:physiology; D051763:PAX7 Transcription Factor; D011247:Pregnancy; D015534:Trans-Activators / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D000074290:Zinc Finger Protein Gli3
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001425:Bacterial Outer Membrane Proteins; D051792:Basic Helix-Loop-Helix Proteins; D006690:Bisbenzimidazole; D004268:DNA-Binding Proteins; D005353:Fibronectins; D019922:GAP-43 Protein; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; D051741:Kruppel-Like Transcription Factors; D007797:Laminin; D009419:Nerve Tissue Proteins; D019006:Neural Cell Adhesion Molecules; D051763:PAX7 Transcription Factor; D015534:Trans-Activators; D014157:Transcription Factors; D000074290:Zinc Finger Protein Gli3; C499317:Ascl1 protein, mouse; C465571:Gli3 protein, mouse; C504649:PSIP1 protein, human; C497322:Pax7 protein, mouse; C504650:Psip1 protein, mouse; C465570:Shh protein, mouse; C486336:Neurog1 protein, mouse