Regulation of procollagen amino-propeptide processing during mouse embryogenesis by specialization of homologous ADAMTS proteases: insights on collagen biosynthesis and dermatosparaxis.
2006
Mutations in ADAMTS2, a procollagen amino-propeptidase, cause severe skin
fragility, designated as dermatosparaxis in animals, and a subtype of the
Ehlers-Danlos syndrome (dermatosparactic type or VIIC) in humans. Not all
collagen-rich tissues are affected to the same degree, which suggests
compensation by the ADAMTS2 homologs ADAMTS3 and ADAMTS14. In situ
hybridization of Adamts2, Adamts3 and Adamts14 , and of the
genes encoding the major fibrillar collagens, Col1a1, Col2a1 and
Col3a1 , during mouse embryogenesis, demonstrated distinct
tissue-specific, overlapping expression patterns of the protease and substrate
genes. Adamts3 , but not Adamts2 or Adamts14 , was
co-expressed with Col2a1 in cartilage throughout development, and
with Col1a1 in bone and musculotendinous tissues. ADAMTS3 induced
procollagen I processing in dermatosparactic fibroblasts, suggesting a role in
procollagen I processing during musculoskeletal development. Adamts2 ,
but not Adamts3 or Adamts14 , was co-expressed with
Col3a1 in many tissues including the lungs and aorta, and
Adamts2 -/- mice showed widespread defects in procollagen
III processing. Adamts2 -/- mice had abnormal lungs,
characterized by a decreased parenchymal density. However, the aorta and
collagen fibrils in the aortic wall appeared normal. Although
Adamts14 lacked developmental tissue-specific expression, it was
co-expressed with Adamts2 in mature dermis, which possibly explains
the presence of some processed skin procollagen in dermatosparaxis. The data
show how evolutionarily related proteases with similar substrate preferences
may have distinct biological roles owing to tissue-specific gene expression,
and provide insights into collagen biosynthesis and the pathobiology of
dermatosparaxis.
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