Altered Splicing in Prelamin A-Associated Premature Aging Phenotypes

Sandre-Giovannoli, Annachiara De; Lévy, Nicolas

doi:10.1007/978-3-540-34449-0_9

Cited by 22 publications

(12 citation statements)

References 132 publications

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“…This would be consistent with the recent observation that exclusive expression of farnesylatable progerin elicited a relatively more severe progeroid phenotypes than those of its non-farnesylated form in knock-in mice [37]. On the other hand, exclusively expressed non-farnesylated prelamin A still induced prominent cardiomyopathy but not progeria in knock-in mice, whereas the survival of such mice which exclusively produce farnesylatable prelamin A was very similar to that of wild-type mice [38], which is quite possibly due to the lower amount of farnesylated prelamin A. Embryonic senescence and further unforeseen developmental abnormalities may also be occurring in human (or mice) progeria given that severe neonatal lethality has been reported [15] [77] [78].…”

Section: Discussionmentioning

confidence: 97%

Embryonic Senescence and Laminopathies in a Progeroid Zebrafish Model

Koshimizu

Imamura

et al. 2011

PLoS ONE

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BackgroundMutations that disrupt the conversion of prelamin A to mature lamin A cause the rare genetic disorder Hutchinson-Gilford progeria syndrome and a group of laminopathies. Our understanding of how A-type lamins function in vivo during early vertebrate development through aging remains limited, and would benefit from a suitable experimental model. The zebrafish has proven to be a tractable model organism for studying both development and aging at the molecular genetic level. Zebrafish show an array of senescence symptoms resembling those in humans, which can be targeted to specific aging pathways conserved in vertebrates. However, no zebrafish models bearing human premature senescence currently exist.Principal FindingsWe describe the induction of embryonic senescence and laminopathies in zebrafish harboring disturbed expressions of the lamin A gene (LMNA). Impairments in these fish arise in the skin, muscle and adipose tissue, and sometimes in the cartilage. Reduced function of lamin A/C by translational blocking of the LMNA gene induced apoptosis, cell-cycle arrest, and craniofacial abnormalities/cartilage defects. By contrast, induced cryptic splicing of LMNA, which generates the deletion of 8 amino acid residues lamin A (zlamin A-Δ8), showed embryonic senescence and S-phase accumulation/arrest. Interestingly, the abnormal muscle and lipodystrophic phenotypes were common in both cases. Hence, both decrease-of-function of lamin A/C and gain-of-function of aberrant lamin A protein induced laminopathies that are associated with mesenchymal cell lineages during zebrafish early development. Visualization of individual cells expressing zebrafish progerin (zProgerin/zlamin A-Δ37) fused to green fluorescent protein further revealed misshapen nuclear membrane. A farnesyltransferase inhibitor reduced these nuclear abnormalities and significantly prevented embryonic senescence and muscle fiber damage induced by zProgerin. Importantly, the adult Progerin fish survived and remained fertile with relatively mild phenotypes only, but had shortened lifespan with obvious distortion of body shape.ConclusionWe generated new zebrafish models for a human premature aging disorder, and further demonstrated the utility for studying laminopathies. Premature aging could also be modeled in zebrafish embryos. This genetic model may thus provide a new platform for future drug screening as well as genetic analyses aimed at identifying modifier genes that influence not only progeria and laminopathies but also other age-associated human diseases common in vertebrates.

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Section: Discussionmentioning

confidence: 97%

Embryonic Senescence and Laminopathies in a Progeroid Zebrafish Model

Koshimizu

Imamura

et al. 2011

PLoS ONE

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“…The changes in splicing lead to the production of truncated protein products (p.G608G, p.T623S and IVS11+1G>A). Most of the typical Hutchinson-Gilford progeria cases are due to a recurrent, de novo point mutation in LMNA exon 11: c.1824C>T [93]. This mutation occurs in a probable exon splicing enhancer.…”

Section: Examples Of Diseases Caused By Alternative Splicingmentioning

confidence: 99%

Alternative splicing and disease

Tazi

Bakkour

Stamm

2009

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

481

365

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Almost all protein-coding genes are spliced and their majority is alternatively spliced. Alternative splicing is a key element in eukaryotic gene expression that increases the coding capacity of the human genome and an increasing number of examples illustrates that the selection of wrong splice sites causes human disease. A fine-tuned balance of factors regulates splice site selection. Here, we discuss well-studied examples that show how a disturbance of this balance can cause human disease. The rapidly emerging knowledge of splicing regulation now allows the development of treatment options.

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“…In particular, it is plausible that the loss/decrease of plasticity and/or onset of self-renewal defects in mesenchymal stem cells may be responsible for the specificity of accelerated tissue degeneration, as most affected tissues in progeria are of mesenchymal origin (Scaffidi and Misteli, 2008). Embryonic senescence and further unforeseen developmental abnormalities may also be occurring in human (or mice) progeria given that severe neonatal lethality has been reported (Rodriguez et al, 1999;van Engelen et al, 2005;De Sandre-Giovannoli and Levy, 2006).…”

Section: Progeroid Zebrafish As a Model Of Human Progeriamentioning

confidence: 95%

The search for evolutionary developmental origins of aging in zebrafish: A novel intersection of developmental and senescence biology in the zebrafish model system

Kishi

2011

Birth Defects Research Pt C

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Senescence may be considered the antithesis of early development, but yet there may be factors and mechanisms in common between these two phenomena during the process of aging. We investigated whether any relationship exists between the regulatory mechanisms that function in early development and in senescence using the zebrafish (Danio rerio), a small freshwater fish and a useful model animal for genetic studies. We conducted experiments to isolate zebrafish mutants expressing an apparent senescence phenotype during embryogenesis (embryonic senescence). Some of the genes we thereby identified had already been associated with cellular senescence and chronological aging in other organisms, but many had not yet been linked to these processes. Complete loss-of-function of developmentally essential genes induce embryonic (or larval) lethality, whereas it seems like their partial loss-of-function (i.e., decrease-of-function by heterozygote or hypomorphic mutations) still remains sufficient to go through the early developmental process because of its adaptive plasticity or rather heterozygote advantage. However, in some cases, such partial loss-of-function of genes compromise normal homeostasis due to haploinsufficiency later in adult life having many environmental stress challenges. By contrast, any heterozygote-advantageous genes might gain a certain benefit(s) (much more fitness) by such partial loss-of-function later in life. Physiological senescence may evolutionarily arise from both genetic and epigenetic drifts as well as from losing adaptive developmental plasticity in face of stress signals from the external environment that interacts with functions of multiple genes rather than effects of only a single gene mutation or defect. Previously uncharacterized developmental genes may thus mediate the aging process and play a pivotal role in senescence. Moreover, unexpected senescence-related genes might also be involved in the early developmental process and regulation. We wish to ascertain whether we can identify such genes promptly in a comprehensive manner. The ease of manipulation using the zebrafish system allows us to conduct an exhaustive exploration of novel genes and small molecular compounds that can be linked to the senescence phenotype and thereby facilitates searching for the evolutionary and developmental origins of aging in vertebrates.

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Altered Splicing in Prelamin A-Associated Premature Aging Phenotypes

Cited by 22 publications

References 132 publications

Embryonic Senescence and Laminopathies in a Progeroid Zebrafish Model

Embryonic Senescence and Laminopathies in a Progeroid Zebrafish Model

Alternative splicing and disease

The search for evolutionary developmental origins of aging in zebrafish: A novel intersection of developmental and senescence biology in the zebrafish model system

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