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First published online 17 September 2008
doi: 10.1242/dev.012237

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Eya4 regulation of Na⁺/K⁺-ATPase is required for sensory system development in zebrafish

Libin Wang^1,2, William F. Sewell³, Sang D. Kim¹, Jordan T. Shin⁴, Calum A. MacRae⁴, Leonard I. Zon^2,5, J. G. Seidman^1,2,* and Christine E. Seidman^1,2,*,

¹ Harvard Medical School, Department of Genetics, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
² Howard Hughes Medical Institute, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
³ Department of Otolaryngology and Program in Neuroscience, Harvard Medical School and MEEI, Boston, MA 02114, USA.
⁴ Developmental Biology Laboratory and Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA 02129, USA.
⁵ Stem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston and Dana-Farber Cancer Institute, 300 Longwood Avenue, Boston, MA 02115, USA.

Author for correspondence (e-mail: cseidman{at}genetics.med.harvard.edu)

Accepted 13 August 2008

To investigate the mechanisms by which mutations in the human transcriptional co-activator EYA4 gene cause sensorineural hearing loss that can occur in association with dilated cardiomyopathy, we studied eya4 expression during zebrafish development and characterized eya4 deficiency. eya4 morphant fish embryos had reduced numbers of hair cells in the otic vesicle and lateral line neuromasts with impaired sensory responses. Analyses of candidate genes that are known to be expressed in a temporal and spatial pattern comparable to eya4 focused our analyses on atp1b2b, which encodes the β2b subunit of the zebrafish Na⁺/K⁺-ATPase. We demonstrate atp1b2b levels are reduced in eya4 morphant fish and that morpholino oligonucleotides targeting the atp1b2b gene recapitulated the eya4 deficiency phenotypes, including heart failure, decreased sensory hair cell numbers in the otic vesicle and neuromasts, and abnormal sensory responses. Furthermore, atp1b2b overexpression rescued these phenotypes in eya4 morphant fish. We conclude that eya4 regulation of Na⁺/K⁺-ATPase is crucial for the development of mechanosensory cells and the maintenance of cardiac function in zebrafish.

Key words: Eya4, Na⁺/K⁺-ATPase, Hair cells, Myocardium, Neuromast, Otic vesicle

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