Characterization of lamin Mutation Phenotypes in Drosophila and Comparison to Human Laminopathies

Abstract

Lamins are intermediate filament proteins that make up the nuclear lamina, a matrix underlying the nuclear membrane in all metazoan cells that is important for nuclear form and function. Vertebrate A-type lamins are expressed in differentiating cells, while B-type lamins are expressed ubiquitously. Drosophila has two lamin genes that are expressed in A- and B-type patterns, and it is assumed that similarly expressed lamins perform similar functions. However, Drosophila and vertebrate lamins are not orthologous, and their expression patterns evolved independently. It is therefore of interest to examine the effects of mutations in lamin genes. Mutations in the mammalian lamin A/C gene cause a range of diseases, collectively called laminopathies, that include muscular dystrophies and premature aging disorders. We compared the sequences of lamin genes from different species, and we have characterized larval and adult phenotypes in Drosophila bearing mutations in the lam gene that is expressed in the B-type pattern. Larvae move less and show subtle muscle defects, and surviving lam adults are flightless and walk like aged wild-type flies, suggesting that lam phenotypes might result from neuromuscular defects, premature aging, or both. The resemblance of Drosophila lam phenotypes to human laminopathies suggests that some lamin functions may be performed by differently expressed genes in flies and mammals. Such still-unknown functions thus would not be dependent on lamin gene expression pattern, suggesting the presence of other lamin functions that are expression dependent. Our results illustrate a complex interplay between lamin gene expression and function through evolution.

Accurate Quantification of Functional Analogy among Close Homologs

“…This is supported by the diverse phenotypes produced by Lam and LamC mutations in Drosophila. Mutations in LamC cause muscle nuclear envelope defects similar to those of the vertebrate A-type lamins [44], while Lam mutations cause locomotion defects and premature aging [45]. Consistent with these observations, our analysis suggests that while LamC is purely a type-A lamin, some type-A functions may be performed (possibly exclusively) by Lam alongside its role as a Type-B lamin, suggesting it could play an important role in understanding human type-A laminopathies.…”

A Comparative Study of Drosophila and Human A-Type Lamins

“…Our studies and those of others suggest that Drosophila will be useful for modeling laminopathies [22], [49]. Here, we focused on Lamin C and discovered many commonalities between the fly and human A-type lamins.…”

The Nuclear Lamina Regulates Germline Stem Cell Niche Organization via Modulation of EGFR Signaling

“…We first analyzed the role of LAM during Drosophila spermatogenesis. Flies harboring the Lam -null allele as Lam D395 / Df(2L)cl-h1 transheterozygotes die during larval and pupal stages with ~6% `escapers' that eclose (Munoz-Alarcon et al, 2007). The surviving adults appeared grossly normal but were male and female sterile.…”