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J. Biol. Chem., Vol. 281, Issue 50, 38592-38598, December 15, 2006

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Actin Filaments Are Required for Fibripositor-mediated Collagen Fibril Alignment in Tendon^*

Elizabeth G. Canty, Tobias Starborg, Yinhui Lu, Sally M. Humphries, David F. Holmes, Roger S. Meadows, Adam Huffman, Eileen T. O'Toole, and Karl E. Kadler¹

From the Wellcome Trust Centre for Cell Matrix Research, Faculty of Life Sciences, University of Manchester, Michael Smith Building, Oxford Road, Manchester M13 9PT, United Kingdom and the Boulder Laboratory for Three-dimensional Electron Microscopy of Cells, Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, Colorado 80309-0347

Cells in tendon deposit parallel arrays of collagen fibrils to form a functional tissue, but how this is achieved is unknown. The cellular mechanism is thought to involve the formation of intracellular collagen fibrils within Golgi to plasma membrane carriers. This is facilitated by the intracellular processing of procollagen to collagen by members of the tolloid and ADAMTS families of enzymes. The carriers subsequently connect to the extracellular matrix via finger-like projections of the plasma membrane, known as fibripositors. In this study we have shown, using three-dimensional electron microscopy, the alignment of fibripositors with intracellular fibrils as well as an orientated cable of actin filaments lining the cytosolic face of a fibripositor. To demonstrate a specific role for the cytoskeleton in coordinating extracellular matrix assembly, cytochalasin was used to disassemble actin filaments and nocodazole or colchicine were used to disrupt microtubules. Microtubule disruption delayed procollagen transport through the secretory pathway, but fibripositor numbers were unaffected. Actin filament disassembly resulted in rapid loss of fibripositors and a subsequent disappearance of intracellular fibrils. Procollagen secretion or processing was not affected by cytochalasin treatment, but the parallelism of extracellular collagen fibrils was altered. In this case a significant proportion of collagen fibrils were found to no longer be orientated with the long axis of the tendon. The results suggest an important role for the actin cytoskeleton in the alignment and organization of the collagenous extracellular matrix in embryonic tendon.

Received for publication, August 9, 2006 , and in revised form, September 18, 2006.

^* This work was supported by The Wellcome Trust and the Biotechnology and Biological Sciences Research Council (to K. E. K.) and in part by Grant RR-00592 to J. R. McIntosh from the National Center for Research Resources of the National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 44-161-275-5086; Fax: 44-161-275-1505; E-mail: karl.kadler{at}manchester.ac.uk.

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