A comparative study of Drosophila and human A-type lamins.
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 Dm(0), 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.
Department of Biology, Western Washington University, Bellingham, Washington, United States of America.
Sandra R
SR
Schulze
Beatrice
B
Curio-Penny
Sean
S
Speese
George
G
Dialynas
Diane E
DE
Cryderman
Caitrin W
CW
McDonough
Demet
D
Nalbant
Melissa
M
Petersen
Vivian
V
Budnik
Pamela K
PK
Geyer
Lori L
LL
Wallrath
D000818:Animals; D030801:Animals, Genetically Modified; D002467:Cell Nucleus / Q000378:metabolism; D004331:Drosophila melanogaster; D005786:Gene Expression Regulation; D006801:Humans; D034904:Lamin Type A / Q000096:biosynthesis / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D009132:Muscles / Q000473:pathology; D009154:Mutation; D009685:Nuclear Envelope / Q000378:metabolism; D014018:Tissue Distribution; D020798:Two-Hybrid System Techniques
D034904:Lamin Type A; C440308:lamin C