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J. Cell Biol.,
Volume 140, Number 5, March 9, 1998 1159-1166
* School of Biological Sciences, University of Manchester, Manchester, M13 9PT, United Kingdom; Mice carrying the Tight skin (Tsk) mutation
harbor a genomic duplication within the fibrillin-1 (Fbn
1) gene that results in a larger than normal in-frame
Fbn 1 transcript. In this study, the consequences of the
Tsk mutation for fibrillin-containing microfibrils have
been examined. Dermal fibroblasts from Tsk/+ mice
synthesized and secreted both normal fibrillin (~330
kD) and the mutant oversized Tsk fibrillin-1 (~450 kD)
in comparable amounts, and Tsk fibrillin-1 was stably
incorporated into cell layers. Immunohistochemical
and ultrastructural analyses of normal and Tsk/+
mouse skin highlighted differences in the gross organization and distribution of microfibrillar arrays. Rotary
shadowing of high Mr preparations from Tsk/+ skin
demonstrated the presence of abundant beaded microfibrils. Some of these had normal morphology and
periodicity, but others were distinguished by diffuse interbeads, longer periodicity, and tendency to aggregate.
The presence of a structurally abnormal population of
microfibrils in Tsk/+ skin was unequivocally demonstrated after calcium chelation and in denaturating conditions. Scanning transmission electron microscopy highlighted the presence of more mass in Tsk/+ skin
microfibrils than in normal mice skin microfibrils.
These data indicate that Tsk fibrillin-1 polymerizes
and becomes incorporated into a discrete population
of beaded microfibrils with altered molecular organization.
Department of
Dermatology, Department of Medical Physics and Biophysics, University of Muenster, D-48149, Germany; and Department
of Microbiology and Immunology, § Department of Medicine, Jefferson Medical College, Thomas Jefferson University,
Philadelphia, Pennsylvania 19107-5541
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