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Barhl1 Regulatory Sequences Required for Cell-Specific Gene Expression and Autoregulation in the Inner Ear and Central Nervous System ^,

Center for Advanced Biotechnology and Medicine and Department of Pediatrics, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey 08854,¹ Department of Biomedical Sciences, Creighton University, Omaha, Nebraska 68178²

Received 11 August 2007/ Returned for modification 8 September 2007/ Accepted 1 January 2008

The development of the nervous system requires the concerted actions of multiple transcription factors, yet the molecular events leading to their expression remain poorly understood. Barhl1, a mammalian homeodomain transcription factor of the BarH class, is expressed by developing inner ear hair cells, cerebellar granule cells, precerebellar neurons, and collicular neurons. Targeted gene inactivation has demonstrated a crucial role for Barhl1 in the survival and/or migration of these sensory cells and neurons. Here we report the regulatory sequences of Barhl1 necessary for directing its proper spatiotemporal expression pattern in the inner ear and central nervous system (CNS). Using a transgenic approach, we have found that high-level and cell-specific expression of Barhl1 within the inner ear and CNS depends on both its 5' promoter and 3' enhancer sequences. Further transcriptional, binding, and mutational analyses of the 5' promoter have identified two homeoprotein binding motifs that can be occupied and activated by Barhl1. Moreover, proper Barhl1 expression in inner ear hair cells and cerebellar and precerebellar neurons requires the presence of Atoh1. Together, these data delineate useful Barhl1 regulatory sequences that direct strong and specific gene expression to inner ear hair cells and CNS sensory neurons, establish a role for autoregulation in the maintenance of Barhl1 expression, and identify Atoh1 as a key upstream regulator.

Published ahead of print on 22 January 2008.

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