Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 21, Pages E1923-E1932Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1303916110
Keywords
nucleokinesis; CaaX motif; posttranslational modification; genetically modified mouse models
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Funding
- National Institutes of Health [HL86683, HL089781, AG035626]
- Ellison Medical Foundation Senior Scholar Program
- Scientist Development grant from the American Heart Association
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The role of protein farnesylation in lamin A biogenesis and the pathogenesis of progeria has been studied in considerable detail, but the importance of farnesylation for the B-type lamins, lamin B1 and lamin B2, has received little attention. Lamins B1 and B2 are expressed in nearly every cell type from the earliest stages of development, and they have been implicated in a variety of functions within the cell nucleus. To assess the importance of protein farnesylation for B-type lamins, we created knock-in mice expressing nonfarnesylated versions of lamin B1 and lamin B2. Mice expressing nonfarnesylated lamin B2 developed normally and were free of disease. In contrast, mice expressing nonfarnesylated lamin B1 died soon after birth, with severe neurodevelopmental defects and striking nuclear abnormalities in neurons. The nuclear lamina in migrating neurons was pulled away from the chromatin so that the chromatin was left naked (free from the nuclear lamina). Thus, farnesylation of lamin B1-but not lamin B2-is crucial for brain development and for retaining chromatin within the bounds of the nuclear lamina during neuronal migration.
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