Tau isoforms which contain the domain encoded by exon 6 and their role in neurite elongation

Luo, Min‐Hua; Leski, Michael; Andreadis, Athena

doi:10.1002/jcb.20029

Cited by 23 publications

(34 citation statements)

References 56 publications

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“…Tissue‐specific alternative splicing profoundly affects physiology, development and disease, and this is nowhere more evident than in the nervous system (Lipscombe 2005). Our previous work showed that tau exon 6 has a unique expression pattern which differs from that of all other tau‐regulated exons (Wei and Andreadis 1998; Luo et al . 2004a,b).…”

Section: Discussionmentioning

confidence: 99%

Tau exon 6 is regulated by an intricate interplay of trans factors and cis elements, including multiple branch points

Wang

Tse

Andreadis

2006

Journal of Neurochemistry

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Tau is a microtubule-associated protein whose transcript undergoes complex regulated splicing in the mammalian nervous system. Exon 6 of the gene is an alternatively spliced cassette whose expression profile differs from that of the other tau regulated exons, implying the involvement of distinct regulatory factors. Previous work had established the existence and use of two additional 3¢ splice sites within exon 6 and the influence of splicing factors polypyrimidine binding protein (PTB) and U2AF on its splicing. The present work shows that exon 6 isoforms exist in distinct ratios in different compartments of the nervous system and that splicing of exon 6 is governed by multiple branch points, exonic cis elements and additional trans factors. Recent results show that tau exon 6 is specifically suppressed in the brains of people who suffer from myotonic dystrophy type 1. The understanding of how tau exon 6 splicing is regulated may give us insights into the disease. Keywords alternative splicing, cis regulatory elements, cryptic splice site, microtubule-associated protein tau, myotonic dystrophy, trans splicing regulators.

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Section: Discussionmentioning

confidence: 99%

Tau exon 6 is regulated by an intricate interplay of trans factors and cis elements, including multiple branch points

Wang

Tse

Andreadis

2006

Journal of Neurochemistry

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“…To detect the cellular proteins used as markers for NPCs, astroglia, and neurons, we slightly modified this fixation/permeabilization protocol. The permeabilization time in 1% Triton X-100 was extended from 5 min to 10 min to access cytoskeletal proteins more efficiently (19). After Ag detection, coverslips were mounted in glycerol containing paraphenylene diamine to inhibit photobleaching.…”

Section: Methodsmentioning

confidence: 99%

Neonatal Neural Progenitor Cells and Their Neuronal and Glial Cell Derivatives Are Fully Permissive for Human Cytomegalovirus Infection

Luo

Schwartz

Fortunato

2008

J Virol

123

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Congenital human cytomegalovirus (HCMV) infection causes central nervous system structural abnormalities and functional disorders, affecting both astroglia and neurons with a pathogenesis that is only marginally understood. To better understand HCMV's interactions with such clinically important cell types, we utilized neural progenitor cells (NPCs) derived from neonatal autopsy tissue, which can be differentiated down either glial or neuronal pathways. Studies were performed using two viral isolates, Towne (laboratory adapted) and TR (a clinical strain), at a multiplicity of infection of 3. NPCs were fully permissive for both strains, expressing the full range of viral antigens (Ags) and producing relatively large numbers of infectious virions. NPCs infected with TR showed delayed development of cytopathic effects (CPE) and replication centers and shed less virus. This pattern of delay for TR infections held true for all cell types tested. Differentiation of NPCs was carried out for 21 days to obtain either astroglia (>95% GFAP ؉ ) or a 1:5 mixed neuron/astroglia population (␤-tubulin III ؉ /GFAP ؉ ). We found that both of these differentiated populations were fully permissive for HCMV infection and produced substantial numbers of infectious virions. Utilizing a difference in plating efficiencies, we were able to enrich the neuron population to ϳ80% ␤-tubulin III ؉ cells. These ␤-tubulin III ؉ -enriched populations remained fully permissive for infection but were very slow to develop CPE. These infected enriched neurons survived longer than either NPCs or astroglia, and a small proportion were alive until at least 14 days postinfection. These surviving cells were all ␤-tubulin III ؉ and showed viral Ag expression. Surprisingly, some cells still exhibited extended processes, similar to mock-infected neurons. Our findings strongly suggest neurons as reservoirs for HCMV within the developing brain.Human cytomegalovirus (HCMV) is a ubiquitous betaherpesvirus that is the most common cause of virus-induced birth defects. Primary infection during pregnancy poses a 30 to 40% risk of intrauterine transmission, with adverse outcomes more likely if the infection is within the first half of the gestation period (37). Each year, about 1% of all newborns are congenitally infected, and 5 to 10% of these infants manifest signs of serious neurological defects, including deafness, mental retardation, blindness, microencephaly, hydrocephalus, and cerebral calcification (1, 3, 37). An additional 10% of congenitally infected infants are asymptomatic at birth and subsequently develop brain disorders, the most common of which is sensorineural hearing loss (7, 27). Thus, in the United States, some 8,000 children annually suffer the obvious consequences of congenital HCMV infection. Additionally, recent investigations have suggested that more subtle abnormal changes in human brain development, such as autism (with an incidence of 1:200), may in some cases be related to congenital HCMV infection (38,43).Although HCMV has a wide range of ...

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“…However, the impact of the exon 6c-encoded sequence on Tau phosphorylation is yet unknown. Although Tau containing exon 6c-encoded sequence binds microtubules, it might serve as an inhibitor of axon elongation, particularly when the Tau isoforms also contain exon 2- and exon 3-encoded sequences (Luo et al, 2004a,b). …”

Section: Dm1 and Tau Mis-splicingmentioning

confidence: 99%

Brain pathology in myotonic dystrophy: when tauopathy meets spliceopathy and RNAopathy

Caillet-Boudin

Fernandez-Gomez

Tran

et al. 2014

Front. Mol. Neurosci.

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Myotonic dystrophy (DM) of type 1 and 2 (DM1 and DM2) are inherited autosomal dominant diseases caused by dynamic and unstable expanded microsatellite sequences (CTG and CCTG, respectively) in the non-coding regions of the genes DMPK and ZNF9, respectively. These mutations result in the intranuclear accumulation of mutated transcripts and the mis-splicing of numerous transcripts. This so-called RNA gain of toxic function is the main feature of an emerging group of pathologies known as RNAopathies. Interestingly, in addition to these RNA inclusions, called foci, the presence of neurofibrillary tangles (NFT) in patient brains also distinguishes DM as a tauopathy. Tauopathies are a group of nearly 30 neurodegenerative diseases that are characterized by intraneuronal protein aggregates of the microtubule-associated protein Tau (MAPT) in patient brains. Furthermore, a number of neurodegenerative diseases involve the dysregulation of splicing regulating factors and have been characterized as spliceopathies. Thus, myotonic dystrophies are pathologies resulting from the interplay among RNAopathy, spliceopathy, and tauopathy. This review will describe how these processes contribute to neurodegeneration. We will first focus on the tauopathy associated with DM1, including clinical symptoms, brain histology, and molecular mechanisms. We will also discuss the features of DM1 that are shared by other tauopathies and, consequently, might participate in the development of a tauopathy. Moreover, we will discuss the determinants common to both RNAopathies and spliceopathies that could interfere with tau-related neurodegeneration.

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Tau isoforms which contain the domain encoded by exon 6 and their role in neurite elongation

Cited by 23 publications

References 56 publications

Tau exon 6 is regulated by an intricate interplay of trans factors and cis elements, including multiple branch points

Tau exon 6 is regulated by an intricate interplay of trans factors and cis elements, including multiple branch points

Neonatal Neural Progenitor Cells and Their Neuronal and Glial Cell Derivatives Are Fully Permissive for Human Cytomegalovirus Infection

Brain pathology in myotonic dystrophy: when tauopathy meets spliceopathy and RNAopathy

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