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Loss of A-type lamin expression compromises nuclear envelope integrity leading to muscular dystrophy.

Sullivan T, Escalante-Alcalde D, Bhatt H, Anver M, Bhat N, Nagashima K, Stewart CL, Burke B - J. Cell Biol. (1999)

Bottom Line: Whereas B-type lamins are found in all mammalian cells, A-type lamin expression is developmentally regulated.This phenotype is associated with ultrastructural perturbations to the nuclear envelope.In skeletal and cardiac muscles, this is manifest as a dystrophic condition related to EDMD.

View Article: PubMed Central - PubMed

Affiliation: Advanced BioScience Laboratories-Basic Research Program, National Cancer Institute-Frederick Cancer Research and Development Center, Maryland 21702, USA.

ABSTRACT
The nuclear lamina is a protein meshwork lining the nucleoplasmic face of the inner nuclear membrane and represents an important determinant of interphase nuclear architecture. Its major components are the A- and B-type lamins. Whereas B-type lamins are found in all mammalian cells, A-type lamin expression is developmentally regulated. In the mouse, A-type lamins do not appear until midway through embryonic development, suggesting that these proteins may be involved in the regulation of terminal differentiation. Here we show that mice lacking A-type lamins develop to term with no overt abnormalities. However, their postnatal growth is severely retarded and is characterized by the appearance of muscular dystrophy. This phenotype is associated with ultrastructural perturbations to the nuclear envelope. These include the mislocalization of emerin, an inner nuclear membrane protein, defects in which are implicated in Emery-Dreifuss muscular dystrophy (EDMD), one of the three major X-linked dystrophies. Mice lacking the A-type lamins exhibit tissue-specific alterations to their nuclear envelope integrity and emerin distribution. In skeletal and cardiac muscles, this is manifest as a dystrophic condition related to EDMD.

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Electron microscopic analysis of MEFs (a) and hepatocytes (b). (a) In the wild-type and heterozygous MEF nuclei, a largely continuous layer of heterochromatin in contact with the inner face of the nuclear envelope is visible. In the Lmna  nuclei, there are obvious discontinuities in this layer (orange box) that are juxtaposed to distensions of the nuclear membranes. (b) Similar discontinuities can be seen in the liver nuclei (arrow).
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Figure 3: Electron microscopic analysis of MEFs (a) and hepatocytes (b). (a) In the wild-type and heterozygous MEF nuclei, a largely continuous layer of heterochromatin in contact with the inner face of the nuclear envelope is visible. In the Lmna nuclei, there are obvious discontinuities in this layer (orange box) that are juxtaposed to distensions of the nuclear membranes. (b) Similar discontinuities can be seen in the liver nuclei (arrow).

Mentions: These results were confirmed by immunocytochemistry since neither of the two anti–lamin A/C antibodies labeled the NEs of the Lmna −/− MEFs (Fig. 2 a). In contrast, lamins B1 and B2 were readily detected (Fig. 2d and Fig. e). These labeling experiments also revealed dramatic changes in nuclear morphology. Whereas nuclei of wild-type MEFs are roughly circular or slightly ovoid, those of Lmna −/− MEFs are often highly elongated or irregular and exhibit loss of B-type lamins from one pole (Fig. 2d and Fig. e). Although the nuclei remain intact, the overall impression is of large-scale herniation of the nuclear membranes. This abnormality, evident in >80% of the −/− MEF nuclei, is apparent in Fig. 2 e, where Nomarski and lamin B immunofluorescence images are superimposed. Similar results were obtained with antibodies against both the inner nuclear membrane protein LAP2 (Foisner and Gerace 1993) and the nuclear pore complex (NPC) protein Nup153 (Bodoor et al. 1999) (Fig. 2b and Fig. c). The latter also revealed a slight degree of NPC clustering within some −/− nuclear envelopes. An intermediate phenotype was observed for +/− MEFs with frequent elongation of nuclei, but largely normal distribution of nuclear envelope proteins (data not shown). Ultrastructural examination of −/− MEFs and hepatocytes revealed a thinning or loss of heterochromatin at discrete regions of the nuclear face of the INM. These segments of the nuclear envelope, which also lack morphologically identifiable NPCs, likely correspond to the herniations observed in the light microscope (Fig. 3, a and b). Thus, the integrity of NEs in −/− cells is profoundly compromised and shows conclusively for the first time that A-type nuclear lamins are essential for the maintenance of normal nuclear architecture. This complements a previous study in Drosophila showing that a B-type lamin is also essential for nuclear integrity (Lenz-Bohme et al. 1997).


Loss of A-type lamin expression compromises nuclear envelope integrity leading to muscular dystrophy.

Sullivan T, Escalante-Alcalde D, Bhatt H, Anver M, Bhat N, Nagashima K, Stewart CL, Burke B - J. Cell Biol. (1999)

Electron microscopic analysis of MEFs (a) and hepatocytes (b). (a) In the wild-type and heterozygous MEF nuclei, a largely continuous layer of heterochromatin in contact with the inner face of the nuclear envelope is visible. In the Lmna  nuclei, there are obvious discontinuities in this layer (orange box) that are juxtaposed to distensions of the nuclear membranes. (b) Similar discontinuities can be seen in the liver nuclei (arrow).
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Related In: Results  -  Collection

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Figure 3: Electron microscopic analysis of MEFs (a) and hepatocytes (b). (a) In the wild-type and heterozygous MEF nuclei, a largely continuous layer of heterochromatin in contact with the inner face of the nuclear envelope is visible. In the Lmna nuclei, there are obvious discontinuities in this layer (orange box) that are juxtaposed to distensions of the nuclear membranes. (b) Similar discontinuities can be seen in the liver nuclei (arrow).
Mentions: These results were confirmed by immunocytochemistry since neither of the two anti–lamin A/C antibodies labeled the NEs of the Lmna −/− MEFs (Fig. 2 a). In contrast, lamins B1 and B2 were readily detected (Fig. 2d and Fig. e). These labeling experiments also revealed dramatic changes in nuclear morphology. Whereas nuclei of wild-type MEFs are roughly circular or slightly ovoid, those of Lmna −/− MEFs are often highly elongated or irregular and exhibit loss of B-type lamins from one pole (Fig. 2d and Fig. e). Although the nuclei remain intact, the overall impression is of large-scale herniation of the nuclear membranes. This abnormality, evident in >80% of the −/− MEF nuclei, is apparent in Fig. 2 e, where Nomarski and lamin B immunofluorescence images are superimposed. Similar results were obtained with antibodies against both the inner nuclear membrane protein LAP2 (Foisner and Gerace 1993) and the nuclear pore complex (NPC) protein Nup153 (Bodoor et al. 1999) (Fig. 2b and Fig. c). The latter also revealed a slight degree of NPC clustering within some −/− nuclear envelopes. An intermediate phenotype was observed for +/− MEFs with frequent elongation of nuclei, but largely normal distribution of nuclear envelope proteins (data not shown). Ultrastructural examination of −/− MEFs and hepatocytes revealed a thinning or loss of heterochromatin at discrete regions of the nuclear face of the INM. These segments of the nuclear envelope, which also lack morphologically identifiable NPCs, likely correspond to the herniations observed in the light microscope (Fig. 3, a and b). Thus, the integrity of NEs in −/− cells is profoundly compromised and shows conclusively for the first time that A-type nuclear lamins are essential for the maintenance of normal nuclear architecture. This complements a previous study in Drosophila showing that a B-type lamin is also essential for nuclear integrity (Lenz-Bohme et al. 1997).

Bottom Line: Whereas B-type lamins are found in all mammalian cells, A-type lamin expression is developmentally regulated.This phenotype is associated with ultrastructural perturbations to the nuclear envelope.In skeletal and cardiac muscles, this is manifest as a dystrophic condition related to EDMD.

View Article: PubMed Central - PubMed

Affiliation: Advanced BioScience Laboratories-Basic Research Program, National Cancer Institute-Frederick Cancer Research and Development Center, Maryland 21702, USA.

ABSTRACT
The nuclear lamina is a protein meshwork lining the nucleoplasmic face of the inner nuclear membrane and represents an important determinant of interphase nuclear architecture. Its major components are the A- and B-type lamins. Whereas B-type lamins are found in all mammalian cells, A-type lamin expression is developmentally regulated. In the mouse, A-type lamins do not appear until midway through embryonic development, suggesting that these proteins may be involved in the regulation of terminal differentiation. Here we show that mice lacking A-type lamins develop to term with no overt abnormalities. However, their postnatal growth is severely retarded and is characterized by the appearance of muscular dystrophy. This phenotype is associated with ultrastructural perturbations to the nuclear envelope. These include the mislocalization of emerin, an inner nuclear membrane protein, defects in which are implicated in Emery-Dreifuss muscular dystrophy (EDMD), one of the three major X-linked dystrophies. Mice lacking the A-type lamins exhibit tissue-specific alterations to their nuclear envelope integrity and emerin distribution. In skeletal and cardiac muscles, this is manifest as a dystrophic condition related to EDMD.

Show MeSH
Related in: MedlinePlus