B-type lamins are ubiquitously expressed and are essential, while the A-type lamins are believed to be non-essential and are only expressed in differentiated cells. There are two B-type lamins, B1 and B2, expressed from different genes; whereas, the A-type lamins, of which there are 4 isotypes (A and C being the most studied), are products of alternative mRNA splicing (Foisner, 2001)
. Lamin depletion by RNA interference in C. elegans (which have only one B-type lamin) is lethal and associated with a number of phenotypic changes such as uneven clustering of nuclear pore complexes, irregularities in nuclear shape and defects in chromosomal organisation and segregation (Liu et al., 2000)
. In contrast, the lamin A knock-out mouse is born apparently normal, although by eight weeks most transgenic animals die from complications associated with muscular dystrophy and lipodystrophy (Sullivan et al., 1999)
. Thus, it appears that although A-type lamins are not required for development in mammals, they are required to maintain the integrity of a few specific tissues such as muscle and adipose tissue.
Inner Nuclear Membrane Proteins and the Regulation of both Chromatin and Transcription
The lamins and the many of the other INM proteins have been implicated in both chromatin and transcriptional regulation (Foisner, 2001; Wilson et al., 2001)
.
For instance, lamins have been implicated in transcriptional repression through both the interactions of lamin A/C with retinoblastoma protein (Rb) and LBR, which can bind heterochromatin protein 1 (HP1). In addition, both LBR and LAP2b can interact with the chromosomal protein HA95. Several other proteins, including all LAP2 isoforms, emerin and MAN1, contain a distinctive 43 amino acid region called the LEM domain in their N-terminus that can interact with a DNA-bridging protein called BAF. Furthermore, the lamins themselves can interact with core histones via their C-terminal tails (Taniura et al., 1995)
. Recently, the first direct connection between the nuclear lamina and chromatin remodelling has been demonstrated by the discover of the INM protein RFBP, an atypical P-type ATPase that interacts directly with the RUSH family of SWI/SNF-like transcription factors (Mansharamani et al., 2001)
.
The Nuclear Lamina and Disease
Recently, two hereditary forms of Emery-Dreifuss muscular dystrophy (EDMD) have been linked to mutations in either lamins or lamin-associated proteins (reviewed in Morris, 2001)
. The X-linked recessive form of EDMD is caused by mutations in or the loss of emerin, while the autosomal dominant form of EDMD is caused by mutations in lamin A/C. Mutations in lamin A/C also cause one form of dilated cardiomyopathy (CMD1A), one form of limb-girdle muscular dystrophy (LGMD1B), and an unrelated form of lipodystrophy (FPLD). Confirming the role of lamin A/C in these diseases,
the lamin A knock-out mouse exhibits both muscular dystrophy and lipodystrophy (Sullivan et al., 1999)
.
Nuclear Envelope from Gwen Child
EM images the nuclear lamina and lamins (University of Würzburg)
-Image 1 (Human and Xenopus)
-Image 2 (Drosophila)
-Image 3 (Drosophila)
-Immunofluorescence image of emerin
GFP-LBR movie--Jennifer Schwartz, Ph.D.
Published Movies of Nuclear Lamina dynamics
Lamin
B receptor Movies from the Ellenberg et al. 1997 paper (JCB on the
dynamics of Lamin B receptor-GFP in interphase and mitosis.
Broers et al., (1999) Dynamics of the nuclear lamina as monitored
by GFP-tagged A-type lamins.JCS
112: 3463
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