Deficiencies in lamin B1 and lamin B2 cause neurodevelopmental defects and distinct nuclear shape abnormalities in neurons

Coffinier, Catherine; Jung, Hea-Jin; Nobumori, Chika; Chang, Shoou‐Yuh; Tu, Yiping; Barnes, Richard H.; Yoshinaga, Yuko; Jong, Pieter J. de; Vergnes, Laurent; Reue, Karen; Fong, Loren G.; Young, Stephen G.

doi:10.1091/mbc.e11-06-0504

Cited by 201 publications

(327 citation statements)

References 42 publications

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“…Immunohistochemistry studies on the cerebral cortex of Lmnb1 CS/CS embryos revealed abnormal layering of cortical neurons, but the defect was far milder than in Lmnb1 −/− embryos ( Fig. 3K) (24,25). Lmnb1 +/− mice were entirely normal and exhibited no detectable abnormalities in the brain (Fig.…”

Section: Resultsmentioning

confidence: 97%

“…The B-type lamins have been reported to participate in many functions within the cell nucleus, including DNA replication (21) and the formation of the mitotic spindle (22). Recently, both lamin B1 and lamin B2 have been shown to be important for neuronal migration within the developing brain (23)(24)(25)(26). A deficiency of either protein causes abnormal layering of cortical neurons (23,24).…”

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confidence: 99%

“…Recently, both lamin B1 and lamin B2 have been shown to be important for neuronal migration within the developing brain (23)(24)(25)(26). A deficiency of either protein causes abnormal layering of cortical neurons (23,24). Coffinier et al (24) proposed that the neuronal migration defect might be the consequence of impaired integrity of the nuclear lamina.…”

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confidence: 99%

“…A deficiency of either protein causes abnormal layering of cortical neurons (23,24). Coffinier et al (24) proposed that the neuronal migration defect might be the consequence of impaired integrity of the nuclear lamina. Whether the farnesylation of lamin B1 or lamin B2 is important for neuronal migration is not known.…”

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Farnesylation of lamin B1 is important for retention of nuclear chromatin during neuronal migration

Jung¹,

Nobumori²,

Goulbourne³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The role of protein farnesylation in lamin A biogenesis and the pathogenesis of progeria has been studied in considerable detail, but the importance of farnesylation for the B-type lamins, lamin B1 and lamin B2, has received little attention. Lamins B1 and B2 are expressed in nearly every cell type from the earliest stages of development, and they have been implicated in a variety of functions within the cell nucleus. To assess the importance of protein farnesylation for B-type lamins, we created knock-in mice expressing nonfarnesylated versions of lamin B1 and lamin B2. Mice expressing nonfarnesylated lamin B2 developed normally and were free of disease. In contrast, mice expressing nonfarnesylated lamin B1 died soon after birth, with severe neurodevelopmental defects and striking nuclear abnormalities in neurons. The nuclear lamina in migrating neurons was pulled away from the chromatin so that the chromatin was left "naked" (free from the nuclear lamina). Thus, farnesylation of lamin B1-but not lamin B2-is crucial for brain development and for retaining chromatin within the bounds of the nuclear lamina during neuronal migration.genetically modified mouse models T he nuclear lamina is an intermediate filament meshwork that lies beneath the inner nuclear membrane. This lamina provides structural support for the nucleus and also interacts with nuclear proteins and chromatin, thereby affecting many functions within the cell nucleus (1, 2). In mammals, the main protein components of the nuclear lamina are lamins A and C (A-type lamins) and lamins B1 and B2 (B-type lamins).Both B-type lamins and prelamin A (the precursor of lamin A) terminate with a CaaX motif, which triggers three posttranslational modifications (3-5): farnesylation of the carboxyl-terminal cysteine (the "C" in the CaaX motif) (6), endoproteolytic cleavage of the last three amino acids (the -aaX) (7,8), and carboxyl methylation of the newly exposed farnesylcysteine (9, 10). Prelamin A undergoes a second endoproteolytic cleavage event, mediated by zinc metalloproteinase STE24 (ZMPSTE24), which removes 15 additional amino acids from the carboxyl terminus, including the farnesylcysteine methyl ester (11)(12)(13)(14). Lamins B1 and B2 do not undergo the second cleavage step and therefore retain their farnesyl lipid anchor.The discovery that Hutchinson-Gilford progeria syndrome (HGPS) is caused by a LMNA mutation yielding an internally truncated farnesyl-prelamin A (15) has focused interest in the farnesylation of nuclear lamins. This interest has been fueled by the finding that disease phenotypes in mouse models of HGPS could be ameliorated by blocking protein farnesylation with a protein farnesyltransferase inhibitor (FTI) (16)(17)(18)(19). Most recently, children with HGPS seemed to show a positive response to FTI treatment (20).The prospect of using an FTI to treat children with HGPS naturally raises the issue of the importance of protein farnesylation for lamin B1 and lamin B2. The B-type lamins are expressed in all mammalian cells and have been h...

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Section: Resultsmentioning

confidence: 97%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Farnesylation of lamin B1 is important for retention of nuclear chromatin during neuronal migration

Jung¹,

Nobumori²,

Goulbourne³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Why such a strategy exists is unknown, but one possibility is that the precursor to lamin A, farnesyl-prelamin A, interferes with lamin B1 and lamin B2, both of which are farnesylated proteins with critical functions in the brain. In recent studies, Coffinier et al (28,29) have shown that the B-type lamins are crucial for neuronal migration and neuronal viability in the brain. It is conceivable that farnesyl-prelamin A-if produced at high levels in the brain-might compete with the B-type lamins for binding sites along the inner nuclear membrane, whereas lamin C would not.…”

Section: Discussionmentioning

confidence: 99%

Regulation of prelamin A but not lamin C by miR-9, a brain-specific microRNA

Jung¹,

Coffinier²,

Choe

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Lamins A and C, alternatively spliced products of the LMNA gene, are key components of the nuclear lamina. The two isoforms are found in similar amounts in most tissues, but we observed an unexpected pattern of expression in the brain. Western blot and immunohistochemistry studies showed that lamin C is abundant in the mouse brain, whereas lamin A and its precursor prelamin A are restricted to endothelial cells and meningeal cells and are absent in neurons and glia. Prelamin A transcript levels were low in the brain, but this finding could not be explained by alternative splicing. In lamin Aonly knockin mice, where alternative splicing is absent and all the output of the gene is channeled into prelamin A transcripts, large amounts of lamin A were found in peripheral tissues, but there was very little lamin A in the brain. Also, in knockin mice expressing exclusively progerin (a toxic form of prelamin A found in Hutchinson-Gilford progeria syndrome), the levels of progerin in the brain were extremely low. Further studies showed that prelamin A expression, but not lamin C expression, is down-regulated by a brain-specific microRNA, miR-9. Expression of miR-9 in cultured cells reduced lamin A expression, and this effect was abolished when the miR-9-binding site in the prelamin A 3′ UTR was mutated. The down-regulation of prelamin A expression in the brain could explain why mouse models of Hutchinson-Gilford progeria syndrome are free of central nervous system pathology.

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Deleterious Mechanical Deformation Selects Mechanoresilient Cancer Cells with Enhanced Proliferation and Chemoresistance

et al. 2023

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Cancer cells in secondary tumors are found to form metastases more efficiently as compared to their primary tumor counterparts. This is partially due to the unfavorable microenvironments encountered by metastasizing cancer cells that result in the survival of a more metastatic phenotype from the original population. However, the role of deleterious mechanical stresses in this change of metastatic potential is unclear. Here, by forcing cancer cells to flow through small capillary-sized constrictions, it is demonstrated that mechanical deformation can select a tumor cell subpopulation that exhibits resilience to mechanical squeezing-induced cell death. Transcriptomic profiling reveals up-regulated proliferation and DNA damage response pathways in this subpopulation, which are further translated into a more proliferative and chemotherapy-resistant phenotype. These results highlight a potential link between the microenvironmental physical stresses and the enhanced malignancy of metastasizing cancer cells which may be utilized as a therapeutic strategy in preventing the metastatic spread of cancer cells.

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Deficiencies in lamin B1 and lamin B2 cause neurodevelopmental defects and distinct nuclear shape abnormalities in neurons

Cited by 201 publications

References 42 publications

Farnesylation of lamin B1 is important for retention of nuclear chromatin during neuronal migration

Farnesylation of lamin B1 is important for retention of nuclear chromatin during neuronal migration

Regulation of prelamin A but not lamin C by miR-9, a brain-specific microRNA

Deleterious Mechanical Deformation Selects Mechanoresilient Cancer Cells with Enhanced Proliferation and Chemoresistance

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