Characterization of olfactory nerve abnormalities in Twirler mice

The sense of smell is perceived by olfactory receptor neurons (ORN) present in the olfactory epithelium located in the posterosuperior aspect of the nasal cavity. The axons of these ORN migrate to the olfactory bulb (OB), forming a nervous layer on the outermost part of the bulb, and finally synapse in glomerular structures in the OB. The ORN are unique in that they are constantly being renewed throughout life. We characterized the defects in the nasal cavity and olfactory nervous supply of Twirler (Tw) mice by histological and immunohistochemical means. Tw homozygotes have previously been shown to present with midfacial abnormalities in the form of clefts of the lip and palate (Lyon, 1958; Gong et al., 2000). We found that in the Tw homozygotes, the OB was abnormally shaped, the skeletal framework underlying the OB was disrupted, and the morphology of the nasal cavity was altered with poorly defined nasal turbinates. Immunohistochemical staining with antibodies that marked nerves in general (PGP 9.5) and mature ORN (omp) in the olfactory epithelium at two different embryonic stages and in newborn mice revealed the stratification of the olfactory epithelium in Tw homozygotes, albeit slightly thinner compared to wildtype. A striking difference in the olfactory epithelium was the lack of differentiation of the ORN in Tw homozygotes and the reduced axonal input to the OB. In Tw homozygotes at 14.5 days of embryonic development, the presence of many mature ORN found randomly in the mesenchyme suggests the loss of olfactory pathfinding cues to the OB. It is believed that the lack of appropriate pathfinding cues observed in the Tw homozygotes was responsible for the OB not having the appropriate trophic effect on the development and maturation of the ORN as had been observed in partially bulbectomized animals. The defects in the Twirler may prove to be a valuable system to analyze problems in olfactory pathfinding and maturation.