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Brn3a is a transcriptional regulator of soma size, target field innervation and axon pathfinding of inner ear sensory neurons

Eric J. Huang^1,*, Wei Liu², Bernd Fritzsch³, Lynne M. Bianchi⁴, Louis F. Reichardt^1, and Mengqing Xiang^2,

¹ Program in Neuroscience, Department of Physiology, and Howard Hughes Medical Institute, University of California, San Francisco, CA 94143, USA
² Graduate Program in Molecular Genetics and Microbiology, Center for Advanced Biotechnology and Medicine, and Department of Pediatrics, UMDNJ-Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA
³ Department of Biomedical Sciences, Creighton University, Omaha, NE 68178, USA
⁴ Neuroscience Program, Oberlin College, Oberlin, OH, USA
^* Present address: Pathology Service, VAMC and Department of Pathology, University of California, San Francisco, CA 94121, USA

Authors for correspondence (e-mail: xiang{at}cabm.rutgers.edu and lfr{at}cgl.ucsf.edu)

Accepted April 18, 2001

The POU domain transcription factors Brn3a, Brn3b and Brn3c are required for the proper development of sensory ganglia, retinal ganglion cells, and inner ear hair cells, respectively. We have investigated the roles of Brn3a in neuronal differentiation and target innervation in the facial-stato-acoustic ganglion. We show that absence of Brn3a results in a substantial reduction in neuronal size, abnormal neuronal migration and downregulation of gene expression, including that of the neurotrophin receptor TrkC, parvalbumin and Brn3b. Selective loss of TrkC neurons in the spiral ganglion of Brn3a^-/- cochlea leads to an innervation defect similar to that of TrkC^-/- mice. Most remarkably, our results uncover a novel role for Brn3a in regulating axon pathfinding and target field innervation by spiral and vestibular ganglion neurons. Loss of Brn3a results in severe retardation in development of the axon projections to the cochlea and the posterior vertical canal as early as E13.5. In addition, efferent axons that use the afferent fibers as a scaffold during pathfinding also show severe misrouting. Interestingly, despite the well-established roles of ephrins and EphB receptors in axon pathfinding, expression of these molecules does not appear to be affected in Brn3a^-/- mice. Thus, Brn3a must control additional downstream genes that are required for axon pathfinding.

Key words: Brn3a, POU domain, Transcription factor, Spiral ganglion, Vestibular ganglion, Innervation, Axon pathfinding, Mouse

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