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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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Histological and immunohistochemical analysis of tissues from Lmna  mice. (a) Wild-type perivertebral muscle showing the peripheral localization of the nuclei in the muscle fibers. (b) Perivertebral muscles from Lmna  mice showing an increase in nuclear number with many centrally located within the muscle fibers (arrows). (c) Wild-type ventricular cardiac muscle. (d) Ventricular muscle from a Lmna  mouse. (e and f) Emerin (upper panels) localization in the skeletal nuclei of wild-type (e) and lamin −/− (f) mice. In the −/− muscle, the signal intensity of emerin in the NE is weaker than in the +/+ nuclei. Anti–lamin B labeling is unchanged (lower panels rhodamine label). (g and h) Emerin staining in the cardiac nuclei of wild-type (g) and lmna −/− (h) mice. Note the polar distribution (arrows) of emerin in the −/− cardiac muscle NEs. (i and j) Emerin staining in the tongue epithelium. In wild-type epithelium, emerin localization to the NE is readily detectable (i), whereas in the lamin  mice it is lost (j). Nuclei i and j are costained with DAPI.
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Figure 4: Histological and immunohistochemical analysis of tissues from Lmna mice. (a) Wild-type perivertebral muscle showing the peripheral localization of the nuclei in the muscle fibers. (b) Perivertebral muscles from Lmna mice showing an increase in nuclear number with many centrally located within the muscle fibers (arrows). (c) Wild-type ventricular cardiac muscle. (d) Ventricular muscle from a Lmna mouse. (e and f) Emerin (upper panels) localization in the skeletal nuclei of wild-type (e) and lamin −/− (f) mice. In the −/− muscle, the signal intensity of emerin in the NE is weaker than in the +/+ nuclei. Anti–lamin B labeling is unchanged (lower panels rhodamine label). (g and h) Emerin staining in the cardiac nuclei of wild-type (g) and lmna −/− (h) mice. Note the polar distribution (arrows) of emerin in the −/− cardiac muscle NEs. (i and j) Emerin staining in the tongue epithelium. In wild-type epithelium, emerin localization to the NE is readily detectable (i), whereas in the lamin mice it is lost (j). Nuclei i and j are costained with DAPI.

Mentions: Histological analysis of homozygotes revealed that the majority of their internal organs were normal, although some thymic atrophy and a reduction in spleen size was evident as was an absence of white fat, possibly as a secondary consequence of physiological stress. The wild-type and heterozygous mice exhibited no overt abnormalities. Examination of the musculature of the homozygote s revealed that the perivertebral muscles and those surrounding the femur (rectus femoris and semimembranous) were dystrophic. The involvement of individual fibers within each muscle was not uniform with those proximal to the bone being the most severely impaired. Many of these were atrophic with others exhibiting signs of degeneration with hyalin or flocculent cytoplasm. The dystrophic muscle fibers also exhibited variations in diameter, plus an increase in the number of nuclei with some being centrally located within the fibers (Fig. 4 b). Muscles of the head, tongue, and diaphragm were largely unaffected. In the heart, the ventricular muscle was most severely compromised although myocyte involvement was nonuniform. Some were of normal size, but had degenerated with condensed or flocculent eosinophilic or vacuolated cytoplasm (Fig. 4 d). These were often associated with patchy mineralization. Other cardiac myocytes were clearly atrophic. The Lmna mice did not exhibit elevated serum creatine kinase levels, a feature associated with some but not all forms of muscular dystrophy (data not shown) (Bulfield et al. 1984). Overall, the Lmna −/− mice develop a cardiac and skeletal myopathy bearing a striking resemblance to human EDMD (Wehnert and Muntoni 1999).


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)

Histological and immunohistochemical analysis of tissues from Lmna  mice. (a) Wild-type perivertebral muscle showing the peripheral localization of the nuclei in the muscle fibers. (b) Perivertebral muscles from Lmna  mice showing an increase in nuclear number with many centrally located within the muscle fibers (arrows). (c) Wild-type ventricular cardiac muscle. (d) Ventricular muscle from a Lmna  mouse. (e and f) Emerin (upper panels) localization in the skeletal nuclei of wild-type (e) and lamin −/− (f) mice. In the −/− muscle, the signal intensity of emerin in the NE is weaker than in the +/+ nuclei. Anti–lamin B labeling is unchanged (lower panels rhodamine label). (g and h) Emerin staining in the cardiac nuclei of wild-type (g) and lmna −/− (h) mice. Note the polar distribution (arrows) of emerin in the −/− cardiac muscle NEs. (i and j) Emerin staining in the tongue epithelium. In wild-type epithelium, emerin localization to the NE is readily detectable (i), whereas in the lamin  mice it is lost (j). Nuclei i and j are costained with DAPI.
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Related In: Results  -  Collection

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Figure 4: Histological and immunohistochemical analysis of tissues from Lmna mice. (a) Wild-type perivertebral muscle showing the peripheral localization of the nuclei in the muscle fibers. (b) Perivertebral muscles from Lmna mice showing an increase in nuclear number with many centrally located within the muscle fibers (arrows). (c) Wild-type ventricular cardiac muscle. (d) Ventricular muscle from a Lmna mouse. (e and f) Emerin (upper panels) localization in the skeletal nuclei of wild-type (e) and lamin −/− (f) mice. In the −/− muscle, the signal intensity of emerin in the NE is weaker than in the +/+ nuclei. Anti–lamin B labeling is unchanged (lower panels rhodamine label). (g and h) Emerin staining in the cardiac nuclei of wild-type (g) and lmna −/− (h) mice. Note the polar distribution (arrows) of emerin in the −/− cardiac muscle NEs. (i and j) Emerin staining in the tongue epithelium. In wild-type epithelium, emerin localization to the NE is readily detectable (i), whereas in the lamin mice it is lost (j). Nuclei i and j are costained with DAPI.
Mentions: Histological analysis of homozygotes revealed that the majority of their internal organs were normal, although some thymic atrophy and a reduction in spleen size was evident as was an absence of white fat, possibly as a secondary consequence of physiological stress. The wild-type and heterozygous mice exhibited no overt abnormalities. Examination of the musculature of the homozygote s revealed that the perivertebral muscles and those surrounding the femur (rectus femoris and semimembranous) were dystrophic. The involvement of individual fibers within each muscle was not uniform with those proximal to the bone being the most severely impaired. Many of these were atrophic with others exhibiting signs of degeneration with hyalin or flocculent cytoplasm. The dystrophic muscle fibers also exhibited variations in diameter, plus an increase in the number of nuclei with some being centrally located within the fibers (Fig. 4 b). Muscles of the head, tongue, and diaphragm were largely unaffected. In the heart, the ventricular muscle was most severely compromised although myocyte involvement was nonuniform. Some were of normal size, but had degenerated with condensed or flocculent eosinophilic or vacuolated cytoplasm (Fig. 4 d). These were often associated with patchy mineralization. Other cardiac myocytes were clearly atrophic. The Lmna mice did not exhibit elevated serum creatine kinase levels, a feature associated with some but not all forms of muscular dystrophy (data not shown) (Bulfield et al. 1984). Overall, the Lmna −/− mice develop a cardiac and skeletal myopathy bearing a striking resemblance to human EDMD (Wehnert and Muntoni 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.

Show MeSH
Related in: MedlinePlus