Embryonic Lethality of Molecular Chaperone Hsp47 Knockout Mice Is Associated with Defects in Collagen Biosynthesis

doi:10.1083/jcb.150.6.1499

Published online 18 September 2000. doi:10.1083/jcb.150.6.1499

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© The Rockefeller University Press, 0021-9525/2000/9/1499/ $5.00
The Journal of Cell Biology, Volume 150, Number 6, September 18, 2000 1499-1506

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Embryonic Lethality of Molecular Chaperone Hsp47 Knockout Mice Is Associated with Defects in Collagen Biosynthesis

Naoko Nagai^a, Masanori Hosokawa^b, Shigeyoshi Itohara^c, Eijiro Adachi^d, Takatoshi Matsushita^b, Nobuko Hosokawa^a, and Kazuhiro Nagata^a
^a Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation (JST), and Department of Molecular and Cellular Biology, Institute for Frontier Medical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8397, Japan
^b Field of Regeneration Control, Institute for Frontier Medical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8397, Japan
^c Behavioral Genetics Lab, Brain Science Institute (BSI), RIKEN, Wako, Saitama, 351-0198, Japan
^d Department of Molecular Morphology, Kitasato University Graduate School of Medicine, Sagamihara, Kanagawa, 228-8555, Japan

Correspondence to: Kazuhiro Nagata, Department of Molecular and Cellular Biology, Institute for Frontier Medical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8397, Japan. Tel:(81) 75 751 3848

Triple helix formation of procollagen after the assembly ofthree ${alpha}$ -chains at the C-propeptide is a prerequisite for refinedstructures such as fibers and meshworks. Hsp47 is an ER-residentstress inducible glycoprotein that specifically and transientlybinds to newly synthesized procollagens. However, the real functionof Hsp47 in collagen biosynthesis has not been elucidated invitro or in vivo. Here, we describe the establishment of Hsp47knockout mice that are severely deficient in the mature, propeptide-processedform of ${alpha}$ 1(I) collagen and fibril structures in mesenchymal tissues.The molecular form of type IV collagen was also affected, andbasement membranes were discontinuously disrupted in the homozygotes.The homozygous mice did not survive beyond 11.5 days postcoitus(dpc), and displayed abnormally orientated epithelial tissuesand ruptured blood vessels. When triple helix formation of typeI collagen secreted from cultured cells was monitored by proteasedigestion, the collagens of Hsp47+/+ and Hsp47+/- cells wereresistant, but those of Hsp47-/- cells were sensitive. Theseresults indicate for the first time that type I collagen isunable to form a rigid triple-helical structure without theassistance of molecular chaperone Hsp47, and that mice requireHsp47 for normal development.

Key Words: gene targeting, extracellular matrix, collagen fibril, basementmembrane, type I collagen

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