[Abstract Title]. - Society for Neuroscience

259. Cochlear Mechanoreceptors
Time: Sunday, November 16, 2008, 1:00 pm - 5:00 pm
Program#/Poster#: 259.13/BB9
Topic: D.02.a. Mechanoreceptors and cochlea
Support: NIH R01 DC006283
NIH P30 DC04665
NIH T32 DC00022
Title: Valproic acid inhibits sensory epithelia development of the embryonic mouse cochlea
through histone deacetylase inhibition
Authors: *E. L. SLATTERY, J. M. JONES, M. E. WARCHOL;
Otolaryngology, Washington Univ, Sch. Med., St. Louis, MO
Abstract: The developing mouse cochlea undergoes rapid embryonic differentiation that is
accompanied by extensive changes in gene expression (Sajan, S et al., 2007). The aim of the
present study was to examine the role of epigenetic influences on gene expression during
cochlear development. One class of epigenetic gene regulation is mediated by histone
acetylation, which leads to relaxation of DNA coiling and permits increased interaction with
transcriptional protein complexes. Histone acetylation is a dynamic process, and treatment with
histone deacetylase (HDAC) inhibitors leads to maintained histone acetylation, along with
corresponding changes in gene expression. We found that treatment with the HDAC inhibitor
valproic acid (VPA), a commonly used antiepileptic drug, caused decreased differentiation of the
developing sensory epithelium in the mouse cochlea. Embryonic cochleae were dissected from
mice at E13.5, placed in organ culture, and treated for 5 days with 1 mM VPA. This treatment
resulted in a marked disruption of cochlear development. Along the length of the organ of Corti,
we observed scattered sensory regions, which appeared as small patches and were located near
the region that would normally be populated by inner hair cells. The patches contained reduced
numbers of inner hair cells (which lacked stereocilia bundles), no outer hair cells, and decreased
numbers of p75-labeled pillar cells. Expression of Sox2, E-cadherin and Jagged 1 was confined
to cells immediately adjacent to the sensory patches. Cochleae exposed to sodium butyrate and
trichostatin A, biochemically-distinct HDAC inhibitors, possessed similar phenotypes,
suggesting that the effects were due to inhibition of histone deacetylases. Notably, we observed
no increase in pyknotic nuclei following HDAC inhibitor treatment, indicating that the structural
changes were not caused by enhanced cell death in the developing organ of Corti. The results
suggest that histone acetylation status plays an important role in cochlear development.
Disclosures: E.L. Slattery, None; J.M. Jones, None; M.E. Warchol, None.