Abstract
Nuclear intermediate filament proteins, called lamins, form a meshwork that lines the inner surface of the nuclear envelope. Lamins contain three domains: an N-terminal head, a central rod and a C-terminal tail domain possessing an Ig-fold structural motif. Lamins are classified as either A- or B-type based on structure and expression pattern. The Drosophila genome possesses two genes encoding lamins, Lamin C and lamin Dm0, which have been designated A- and B-type, respectively, based on their expression profile and structural features. In humans, mutations in the gene encoding A-type lamins are associated with a spectrum of predominantly tissue-specific diseases known as laminopathies. Linking the disease phenotypes to cellular functions of lamins has been a major challenge. Drosophila is being used as a model system to identify the roles of lamins in development. Towards this end, we performed a comparative study of Drosophila and human A-type lamins. Analysis of transgenic flies showed that human lamins localize predictably within the Drosophila nucleus. Consistent with this finding, yeast two-hybrid data demonstrated conservation of partner-protein interactions. Drosophila lacking A-type lamin show nuclear envelope defects similar to those observed with human laminopathies. Expression of mutant forms of the A-type Drosophila lamin modeled after human disease-causing amino acid substitutions revealed an essential role for the N-terminal head and the Ig-fold in larval muscle tissue. This tissue-restricted sensitivity suggests a conserved role for lamins in muscle biology. In conclusion, we show that (1) localization of A-type lamins and protein-partner interactions are conserved between Drosophila and humans, (2) loss of the Drosophila A-type lamin causes nuclear defects and (3) muscle tissue is sensitive to the expression of mutant forms of A-type lamin modeled after those causing disease in humans. These studies provide new insights on the role of lamins in nuclear biology and support Drosophila as a model for studies of human laminopathies involving muscle dysfunction.
Highlights
Lamins are type V intermediate filament proteins that line the inner surface of the nuclear envelope of animal cells, providing structural support and making contacts with chromatin [1,2]
We examine the evolutionary conservation of human and Drosophila nuclear envelope proteins by expressing human lamins and the LEM domain protein emerin in Drosophila
While Lamin B2 localized to the periphery, small nuclear aggregates were observed. [Human Lamin B1 transgenics were not analyzed by cytology due to the fact that we were unable to identify an antibody that recognized Lamin B1 following expression in Drosophila.]
Summary
Lamins are type V intermediate filament proteins that line the inner surface of the nuclear envelope of animal cells, providing structural support and making contacts with chromatin [1,2]. Humans possess two types of lamins, A- and B-types, which differ in developmental expression patterns and structural properties. Human A-type lamins include Lamin A and Lamin C, alternatively spliced products from the LMNA gene. Human Btype lamins include lamin B1 and Lamin B2, encoded by two separate genes. With the exception of Lamin C, human lamins possess a CaaX box (C, cysteine; a, aliphatic amino acid; X, any amino acid) that becomes prenylated and provides a nuclear envelope anchor. Processed A-type lamins lack a membrane anchor that is possessed by B-type lamins
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