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Mouse B-type lamins are required for proper organogenesis but not by embryonic stem cells.
Science. 2011 Dec 23; 334(6063):1706-10
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19 Dec 2011
New Finding
DOI: 10.3410/f.13409011.14779135
In this excellent paper, Kim et al. generated mouse embryonic stem cells with no B-type lamin proteins. These cells showed no obvious phenotypes. These results challenge previous studies claiming essential cellular roles for B-type lamins. However, B-type lamins were shown to be necessary for normal organogenesis.
Lamins...Continue reading
Lamins...Continue reading
In this excellent paper, Kim et al. generated mouse embryonic stem cells with no B-type lamin proteins. These cells showed no obvious phenotypes. These results challenge previous studies claiming essential cellular roles for B-type lamins. However, B-type lamins were shown to be necessary for normal organogenesis.
Lamins are intermediate filament proteins that are ubiquitously expressed in mammalian cells. They were shown to be essential for many cellular processes in different contexts. Here, Kim et al. generated mouse embryonic stem cells with no lamins due to the knockout of both lamin B genes and the natural lack of expression of lamin A. Surprisingly, no obvious phenotype was observed, extending previous works {1,2} and proving that lamins are not essential for mouse cell proliferation. Knockout mice, however, showed an essential role for lamin B in organogenesis.
B-type lamins probably have additional roles in humans and in Caenorhabditis elegans, since in both organisms they are essential.
Lamins are intermediate filament proteins that are ubiquitously expressed in mammalian cells. They were shown to be essential for many cellular processes in different contexts. Here, Kim et al. generated mouse embryonic stem cells with no lamins due to the knockout of both lamin B genes and the natural lack of expression of lamin A. Surprisingly, no obvious phenotype was observed, extending previous works {1,2} and proving that lamins are not essential for mouse cell proliferation. Knockout mice, however, showed an essential role for lamin B in organogenesis.
B-type lamins probably have additional roles in humans and in Caenorhabditis elegans, since in both organisms they are essential.
References
1.
Null mutants of Drosophila B-type lamin Dm(0) show aberrant tissue differentiation rather than obvious nuclear shape distortion or specific defects during cell proliferation.
Dev Biol 2005 Aug 1; 1(284):219-32
PMID: 15996653
2.
An absence of both lamin B1 and lamin B2 in keratinocytes has no effect on cell proliferation or the development of skin and hair.
Hum Mol Genet 2011 Sep 15; 18(20):3537-44
PMID: 21659336
Disclosures
None declared
Add Comment
Gruenbaum Y and Bar D: F1000Prime Recommendation of [Kim Y et al., Science 2011, 334(6063):1706-10]. In F1000Prime, 19 Dec 2011; DOI: 10.3410/f.13409011.14779135. F1000Prime.com/13409011#eval14779135
10 Jan 2012
Confirmation, Controversial, New Finding
DOI: 10.3410/f.13409011.14815067
I found this article particularly noteworthy since it further forces re-evaluation of the long-held assumption that B-type lamins are essential for cell viability and play an important role in transcriptional repression during differentiation. The authors find that embryonic stem cells lacking all...Continue reading
I found this article particularly noteworthy since it further forces re-evaluation of the long-held assumption that B-type lamins are essential for cell viability and play an important role in transcriptional repression during differentiation. The authors find that embryonic stem cells lacking all lamins differentiate apparently normally in vitro (at least within the first 8 days) and that double-knockout mice for lamins B1 and B2 show mostly normal embryonic development and are viable until birth.
These findings come on the heels of recent, similar reports by Stephen Young and Loren Fong's groups for single lamin B1- {1} and B2-knockout {2} mice, and for a skin-specific double knockout {3}. Taken together, these observations indicate that, while B-type lamins appear dispensable in several tissues, one of the primary roles of B-type lamins, particularly of lamin B1, is in the neuronal migration during brain development, as lamin B1- and/or B2-deficient mice have markedly reduced brain size and abnormal cortical architecture.
Nonetheless, several interesting questions remain to be answered. In addition to the neuronal defects, embryos lacking B-type lamins are overall markedly smaller than wild-type littermates and also show defects in lung architecture. The reasons for these effects remain unclear. Kim et al. hint at the fact that loss of B-type lamins can affect in vivo spindle orientation and thereby tissue development and organogenesis. It will be interesting to follow up on these findings.
Furthermore, Kim et al. confirm that lamin B1-chromatin interactions are closely linked with gene silencing and change during differentiation. Surprisingly then, the lamin B1/B2 double-knockout embryonic stem cells displayed only minimal changes in gene expression during development, and those changes did not correlate with gene associated with lamin B1-interaction sites. Thus, more research will be required to elucidate the mechanism and significance of gene silencing at the nuclear periphery during development.
These findings come on the heels of recent, similar reports by Stephen Young and Loren Fong's groups for single lamin B1- {1} and B2-knockout {2} mice, and for a skin-specific double knockout {3}. Taken together, these observations indicate that, while B-type lamins appear dispensable in several tissues, one of the primary roles of B-type lamins, particularly of lamin B1, is in the neuronal migration during brain development, as lamin B1- and/or B2-deficient mice have markedly reduced brain size and abnormal cortical architecture.
Nonetheless, several interesting questions remain to be answered. In addition to the neuronal defects, embryos lacking B-type lamins are overall markedly smaller than wild-type littermates and also show defects in lung architecture. The reasons for these effects remain unclear. Kim et al. hint at the fact that loss of B-type lamins can affect in vivo spindle orientation and thereby tissue development and organogenesis. It will be interesting to follow up on these findings.
Furthermore, Kim et al. confirm that lamin B1-chromatin interactions are closely linked with gene silencing and change during differentiation. Surprisingly then, the lamin B1/B2 double-knockout embryonic stem cells displayed only minimal changes in gene expression during development, and those changes did not correlate with gene associated with lamin B1-interaction sites. Thus, more research will be required to elucidate the mechanism and significance of gene silencing at the nuclear periphery during development.
References
Disclosures
None declared
Lammerding J: F1000Prime Recommendation of [Kim Y et al., Science 2011, 334(6063):1706-10]. In F1000Prime, 10 Jan 2012; DOI: 10.3410/f.13409011.14815067. F1000Prime.com/13409011#eval14815067
21 Feb 2012
New Finding, Refutation
DOI: 10.3410/f.13409011.14866226
In the world of intermediate filaments (IFs) and related proteins, like the lamins, there have been many functional claims (refs {1} and {2} present a nice overview of some such claims). One problem with these claims is that they often depend upon the phenotypic effects of anti-morphic mutant proteins....Continue reading
In the world of intermediate filaments (IFs) and related proteins, like the lamins, there have been many functional claims (refs {1} and {2} present a nice overview of some such claims). One problem with these claims is that they often depend upon the phenotypic effects of anti-morphic mutant proteins. What is beautiful about this paper is the rigor of the analysis. It clarifies a number of key issues, and should send investigators looking for various lamin-associated (or rather lamin mutant-associated) proteins. By showing that B-type lamins are necessary for proper organogenesis, but not for embryonic stem cells (ESCs) self-renewal and pluripotency, Kim et al. focus attention on a new role for this subset of IFs in tissue organization. It will be interesting to determine whether their role in organogenesis involves effects on the relationship between chromatin organization, patterns of epigenetic modification and gene expression.
What I love about this paper is that it harkens back to early studies on the functions of cytoplasmic IFs, which were often thought to play a number of interesting functional roles. There were even claims of IF function based on the effects of drugs like acrylamide (see ref {3}, on which I am the author). As with this B-lamin paper, only careful examination of null mutations resolves the issue, leaving the (largely structural and mechanical) roles of IFs in specific processes to be clearly defined.
What I love about this paper is that it harkens back to early studies on the functions of cytoplasmic IFs, which were often thought to play a number of interesting functional roles. There were even claims of IF function based on the effects of drugs like acrylamide (see ref {3}, on which I am the author). As with this B-lamin paper, only careful examination of null mutations resolves the issue, leaving the (largely structural and mechanical) roles of IFs in specific processes to be clearly defined.
References
1.
The presence or absence of a vimentin-type intermediate filament network affects the shape of the nucleus in human SW-13 cells.
J Cell Sci 1994 Jun; (107 ( Pt 6)):1593-607
PMID: 7962200
2.
Vimentin: the conundrum of the intermediate filament gene family.
Bioessays 1998 Jan; 1(20):79-86
PMID: 9504050
3.
Metabolic inhibitors and intermediate filament organization in human fibroblasts.
Exp Cell Res 1988 Jan; 1(174):282-90
PMID: 3275545
Disclosures
None declared
Klymkowsky M: F1000Prime Recommendation of [Kim Y et al., Science 2011, 334(6063):1706-10]. In F1000Prime, 21 Feb 2012; DOI: 10.3410/f.13409011.14866226. F1000Prime.com/13409011#eval14866226
F1000Prime Recommendations, Dissents and Comments for [Kim Y et al., Science 2011, 334(6063):1706-10]. In F1000Prime, 21 May 2013; F1000Prime.com/13409011
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B-type lamins, the major components of the nuclear lamina, are believed to be essential for cell proliferation and survival. We found that mouse embryonic stem cells (ESCs) do not need any lamins for self-renewal and pluripotency. Although genome-wide lamin-B binding profiles correlate with reduced gene expression, such binding is not required for gene silencing in ESCs or trophectoderm cells. However, B-type lamins are required for proper organogenesis. Defects in spindle orientation in neural progenitor cells and migration of neurons are most likely the causes of brain disorganizations found in lamin-B null mice. Thus, our studies not only disprove several prevailing views of lamin-Bs but also establish the foundation for redefining the function of the nuclear lamina in the context of tissue building.
PMID: 22116031
