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First published online 6 February 2008
doi: 10.1242/dev.018150

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The ATPase-dependent chaperoning activity of Hsp90a regulates thick filament formation and integration during skeletal muscle myofibrillogenesis

Thomas A. Hawkins¹, Anna-Pavlina Haramis^1,*, Christelle Etard², Chrisostomos Prodromou³, Cara K. Vaughan³, Rachel Ashworth^4,, Saikat Ray¹, Martine Behra^2,, Nigel Holder¹, William S. Talbot⁵, Laurence H. Pearl³, Uwe Strähle² and Stephen W. Wilson^1,

¹ Department of Anatomy and Developmental Biology, UCL, Gower Street, London WC1E 6BT, UK.
² Institute of Toxicology and Genetics, Forschungszentrum Karlsruhe, Postfach 3640, Karlsruhe, D-76021, Germany.
³ Section of Structural Biology, The Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Road, London, SW3 6JB, UK.
⁴ Department of Physiology, UCL, Gower Street, London WC1E 6BT, UK.
⁵ Department of Developmental Biology, Stanford University School of Medicine, Beckman Center B315, 279 Campus Drive, Stanford, CA 94305-5329, USA.

Author for correspondence (e-mail: s.wilson{at}ucl.ac.uk)

Accepted 10 January 2008

The mechanisms that regulate sarcomere assembly during myofibril formation are poorly understood. In this study, we characterise the zebrafish sloth^u45 mutant, in which the initial steps in sarcomere assembly take place, but thick filaments are absent and filamentous I-Z-I brushes fail to align or adopt correct spacing. The mutation only affects skeletal muscle and mutant embryos show no other obvious phenotypes. Surprisingly, we find that the phenotype is due to mutation in one copy of a tandemly duplicated hsp90a gene. The mutation disrupts the chaperoning function of Hsp90a through interference with ATPase activity. Despite being located only 2 kb from hsp90a, hsp90a2 has no obvious role in sarcomere assembly. Loss of Hsp90a function leads to the downregulation of genes encoding sarcomeric proteins and upregulation of hsp90a and several other genes encoding proteins that may act with Hsp90a during sarcomere assembly. Our studies reveal a surprisingly specific developmental role for a single Hsp90 gene in a regulatory pathway controlling late steps in sarcomere assembly.

Key words: Chaperones, Myofibrillogenesis, Zebrafish

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