Lamin B1 mediates cell-autonomous neuropathology in a leukodystrophy mouse model

Heng, Mary Y.; Lin, Shuting; Verret, Laure; Huang, Yong; Kamiya, Sherry; Padiath, Quasar Saleem; Tong, Ying; Palop, Jorge J.; Huang, Eric J.; Ptáček, Louis J.; Fu, Ying‐Hui

doi:10.1172/jci66737

Cited by 66 publications

(96 citation statements)

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“…The transgenic mice manifested cognitive abnormalities, as judged by the Morris water maze test, and progressive motor impairment, as judged by rotarod and balance beam tests. Electroencephalography uncovered frequent spontaneous seizures (79). Myelination defects were not apparent in 12-month-old BAC transgenic mice but were evident by 24 months of age, as judged by electron microscopy.…”

Section: Impact Of Lamin B1 Overexpression In Cultured Cells and In Dmentioning

confidence: 92%

“…The mice also had seizure activity. These abnormalities were accompanied by evidence of demyelination and axonal degeneration (79). Lamin B1 overexpression in oligodendrocytes also led to reduced expression of the major myelin protein, proteolipid protein (PLP), at both the protein and RNA levels (79).…”

Section: Impact Of Lamin B1 Overexpression In Cultured Cells and In Dmentioning

confidence: 99%

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Nuclear Lamins and Neurobiology

Young

Jung

Lee

et al. 2014

Molecular and Cellular Biology

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Much of the work on nuclear lamins during the past 15 years has focused on mutations in LMNA (the gene for prelamin A and lamin C) that cause particular muscular dystrophy, cardiomyopathy, partial lipodystrophy, and progeroid syndromes. These disorders, often called "laminopathies," mainly affect mesenchymal tissues (e.g., striated muscle, bone, and fibrous tissue). Recently, however, a series of papers have identified important roles for nuclear lamins in the central nervous system. Studies of knockout mice uncovered a key role for B-type lamins (lamins B1 and B2) in neuronal migration in the developing brain. Also, duplications of LMNB1 (the gene for lamin B1) have been shown to cause autosome-dominant leukodystrophy. Finally, recent studies have uncovered a peculiar pattern of nuclear lamin expression in the brain. Lamin C transcripts are present at high levels in the brain, but prelamin A expression levels are very low-due to regulation of prelamin A transcripts by microRNA 9. This form of prelamin A regulation likely explains why "prelamin A diseases" such as Hutchinson-Gilford progeria syndrome spare the central nervous system. In this review, we summarize recent progress in elucidating links between nuclear lamins and neurobiology.T he nuclear lamina has attracted considerable scrutiny from biochemists, cell biologists, and geneticists. Much of this attention has been stimulated by the discovery that mutations in LMNA (the gene for the A-type lamins, prelamin A and lamin C) cause multiple human diseases, including muscular dystrophy, cardiomyopathy with conduction system disease, partial lipodystrophy, and progeroid syndromes (1-3). These diseases, often called "laminopathies," are largely confined to mesenchymal tissues. For the past decade, many laboratories have worked to define disease mechanisms and to devise therapeutic strategies. These efforts have been summarized in many reviews (2-11).While "LMNA diseases" have attracted most of the research efforts, a new topic has slowly emerged in the field-nuclear lamin biology in the brain. Three lines of investigation have contributed to the emergence of this topic. The first was work by developmental biologists that uncovered a role for the B-type lamins (lamins B1 and B2) in neuronal migration in the developing brain (12)(13)(14). The second was work showing that a demyelinating disorder, autosomal dominant leukodystrophy, is caused by LMNB1 gene duplications (15, 16). The third was work by clinical investigators to understand the spectrum of disease phenotypes in children with Hutchinson-Gilford progeria syndrome (17, 18), a precocious aging syndrome caused by a toxic form of prelamin A (19). For years, the field marveled that children with progeria have multisystem aging-like phenotypes but are spared common features of physiologic aging in the central nervous system, notably, senile dementia. Recent studies have identified a likely mechanismregulation of prelamin A by a brain-specific microRNA (17, 18). PROTEINS OF THE NUCLEAR LAMINAThe nuclear lamina...

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Section: Impact Of Lamin B1 Overexpression In Cultured Cells and In Dmentioning

confidence: 92%

Section: Impact Of Lamin B1 Overexpression In Cultured Cells and In Dmentioning

confidence: 99%

Nuclear Lamins and Neurobiology

Young

Jung

Lee

et al. 2014

Molecular and Cellular Biology

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“…Excessive lamin B1 expression reduces occupancy of Yin Yang 1 (YY1) transcription factor on the promoter region of PLP, thus leading to down-regulation of PLP abundance, conferring myelin loss in the mouse brain (31). Reduced levels of both PTEN and LMNB1 by miR-23a are likely to participate in hypermyelination observed in the present study.…”

Section: Discussionmentioning

confidence: 59%

MicroRNA-23a promotes myelination in the central nervous system

Lin¹,

Huang

Zhang³

et al. 2013

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

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101

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Demyelinating disorders including leukodystrophies are devastating conditions that are still in need of better understanding, and both oligodendrocyte differentiation and myelin synthesis pathways are potential avenues for developing treatment. Overexpression of lamin B1 leads to leukodystrophy characterized by demyelination of the central nervous system, and microRNA-23 (miR-23) was found to suppress lamin B1 and enhance oligodendrocyte differentiation in vitro. Here, we demonstrated that miR23a-overexpressing mice have increased myelin thickness, providing in vivo evidence that miR-23a enhances both oligodendrocyte differentiation and myelin synthesis. Using this mouse model, we explored possible miR-23a targets and revealed that the phosphatase and tensin homologue/phosphatidylinositol trisphosphate kinase/Akt/mammalian target of rapamycin pathway is modulated by miR-23a. Additionally, a long noncoding RNA, 2700046G09Rik, was identified as a miR-23a target and modulates phosphatase and tensin homologue itself in a miR-23a-dependent manner. The data presented here imply a unique role for miR-23a in the coordination of proteins and noncoding RNAs in generating and maintaining healthy myelin.M icroRNAs (miRNAs) play an important role in regulating a large number of developmental processes and diseases (1-3) through fine tuning biological networks (4, 5). Expression levels of miRNAs in oligodendroglia vary according to their differentiation stages, indicating a possible role for miRNAs in regulating developmental processes among migratory, proliferating, and myelinating oligodendrocytes (OLs) (6-9). Disruption of miRNA biogenesis by Dicer ablation in oligodendroglia at postdevelopmental stages results in a neurodegenerative phenotype including demyelination, inflammation, and axon loss (10), suggesting that miRNAs are also important for myelin maintenance at later developmental stages. miR-23 is among the most abundant miRNAs in OLs (6, 7). Previously, we reported that in the presence of excess miR-23 in vitro, a greater proportion of cells express mature markers of OLs that are paralleled by multipolar morphological appearance with increased levels of mature myelin proteins, indicating that miR-23 can enhance oligodendrogenesis (11). In contrast, excessive lamin B1, a nuclear envelope protein and target of miR-23, leads to lower numbers of cells expressing mature markers with reduced levels of mature myelin proteins both in vitro and in vivo, suggesting defective differentiation of OLs. Importantly, the adverse effects of lamin B1 on OL cells can be abrogated by overexpressing miR-23, which functions as a negative regulator of lamin B1.Here, we use mice in which miR-23a (one of the two miR-23 isoforms: miR-23a and b) overexpression is driven by an OLspecific promoter [2′,3′-cyclic nucleotide 3′-phophodiesterase (Cnp)] to investigate the effects of miR-23a on OL differentiation and myelin synthesis in vivo. We demonstrated that in addition to the previously identified target, lamin B1, miR-23a also directly modul...

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“…They first demonstrated that germline overexpression of lamin B1 replicates most major features of the disease. They then demonstrated overexpression of lamin B1 selectively in oligodendrocytes causes a very similar phenotype, including cognitive impairment, epilepsy, motor deficits and abnormalities of myelin that include the downregulation of proteolipid protein , which is a myelin sheath component [81]. Studies in vitro on cultured cells confirmed a deleterious effect of lamin B1 in oligodendrocytes, in which overexpression of lamin B1 suppressed oligodendrocyte-specific genes and prematurely arrested oligodendrocyte differentiation [82].…”

Section: Central Nervous System Disordersmentioning

confidence: 97%

The Nuclear Envelope: An Intriguing Focal Point for Neurogenetic Disease

Worman

Dauer

2014

Neurotherapeutics

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Mutations in genes encoding nuclear envelope proteins cause a wide range of inherited diseases, many of which are neurological. We review the genetic causes and what little is known about pathogenesis of these nuclear envelopathies that primarily affect striated muscle, peripheral nerve and the central nervous system. We conclude by providing examples of experimental therapeutic approaches to these rare but important neuromuscular diseases.

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Lamin B1 mediates cell-autonomous neuropathology in a leukodystrophy mouse model

Cited by 66 publications

References 50 publications

Nuclear Lamins and Neurobiology

Nuclear Lamins and Neurobiology

MicroRNA-23a promotes myelination in the central nervous system

The Nuclear Envelope: An Intriguing Focal Point for Neurogenetic Disease

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