Nor-1 belongs to the nur subfamily of nuclear receptor transcription factors. The precise role of Nor-1 in mammalian development has not been established. However, recent studies indicate a function for this transcription factor in oncogenesis and apoptosis. To examine the spatiotemporal expression pattern of Nor-1 and the developmental and physiological consequences of Nor-1 ablation, Nor-1-null mice were generated by insertion of the lacZ gene into the Nor-1 genomic locus. Disruption of the Nor-1 gene results in inner ear defects and partial bidirectional circling behavior. During early otic development, Nor-1 is expressed exclusively in the semicircular canal forming fusion plates. After formation of the membranous labyrinth, Nor-1 expression in the vestibule is limited to nonsensory epithelial cells localized at the inner edge of the semicircular canals and to the ampullary and utricular walls. In the absence of Nor-1, the vestibular walls fuse together as normal; however, the endolymphatic fluid space in the semicircular canals is diminished and the roof of the ampulla appears flattened due to defective continual proliferative growth of the semicircular canals.The mouse inner ear develops during the second half of gestation from an otic epithelial vesicle that undergoes a complex series of shape changes to give rise to specific functional compartments including the cochlea, which comprises the auditory apparatus, and the vestibule, which is responsible for sensing motion and gravity. The endolymphatic fluid-filled membranous labyrinth is surrounded by perilymphatic fluid and is contained within an osseous structure (tympanic bone). The vestibular part of the inner ear contains two principal sets of sensory structures, the maculae (saccule and utricle), sensors of linear acceleration and gravity, and the cristae ampullaris, sensors of angular acceleration that are contained within three ampullae. Stimuli related to vestibular functions are produced by movement of the endolymphatic fluid and are recorded by sensory hair cells of the maculae and cristae.Development of the murine inner ear is initiated at E8.5 by the formation of an otic epithelial placode, which arises as a thickening of the head ectoderm between rhombomeres 5 and 6 in the hindbrain, followed by invagination and separation from the ectoderm to become a closed vesicle embedded in the head mesenchyme at E9.5. Structural perturbances begin to occur in the vesicle at E11 to 11.5 with the outgrowth of the ventral wall of the otic vesicle to form a hollow tube that gives rise to the cochlea and a dorsal extension that forms the endolymphatic duct. Cells localized in the dorsolateral walls give rise to the semicircular canals, while the medial and medioventral regions give rise to the utricle and saccule (38). Restricted and asymmetric expression patterns in the otic vesicle have been described for several genes (14, 38) at this developmental stage. These genes then participate in the regional morphogenesis of the inner ear.The semicircular canals or...
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