Regulation of the MID1 protein function is fine-tuned by a complex pattern of alternative splicing

Winter, Jennifer; Lehmann, Tanja; Krauß, Sybille; Trockenbacher, Alexander; Kijas, Zofia; Foerster, John; Suckow, Vanessa; Yaspo, Marie–Laure; Kulozik, Andreas E.; Kalscheuer, Vera M.; Schneider, Rainer; Schweiger, Susann

doi:10.1007/s00439-004-1114-x

Cited by 25 publications

(11 citation statements)

References 25 publications

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“…Furthermore, recombination in F1 hybrids between M. m. castaneus CAST and other subspecies would create Mid1 transcripts that contain a subset of highly diverged M. m. castaneus CAST exons. Mid1 is known to have a large number of tissue-specific splice variants (Winter et al 2004). Combining exons from different subspecies may result in transcripts with altered tissue expression.…”

Section: Discussionmentioning

confidence: 99%

A pronounced evolutionary shift of the pseudoautosomal region boundary in house mice

2012

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The pseudoautosomal region (PAR) is essential for the accurate pairing and segregation of the X and Y chromosomes during meiosis. Despite its functional significance, the PAR shows substantial evolutionary divergence in structure and sequence between mammalian species. An instructive example of PAR evolution is the house mouse Mus musculus domesticus (represented by the C57BL/6J strain), which has the smallest PAR among those that have been mapped. In C57BL/6J, the PAR boundary is located just ~700 kb from the distal end of the X chromosome, whereas the boundary is found at a more proximal position in Mus spretus, a species that diverged from house mice 2–4 million years ago. Here, we use a combination of genetic and physical mapping to document a pronounced shift in the PAR boundary in a second house mouse subspecies, Mus musculus castaneus (represented by the CAST/EiJ strain), ~430 kb proximal of the M. m. domesticus boundary. We demonstrate molecular evolutionary consequences of this shift, including a marked lineage-specific increase in sequence divergence within Mid1, a gene that resides entirely within the M. m. castaneus PAR but straddles the boundary in other subspecies. Our results extend observations of structural divergence in the PAR to closely related subspecies, pointing to major evolutionary changes in this functionally important genomic region over a short time period.

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Section: Discussionmentioning

confidence: 99%

A pronounced evolutionary shift of the pseudoautosomal region boundary in house mice

2012

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“…Alternative splicing is well established to have roles in both regulation of expression and in the generation of protein function diversity, as illustrated by many detailed studies of genes, such as CD44 (36), NOVA (37), ABCC4 (38), MID1 (39) and hUPF2 (40). Although exact estimates vary, it is also clear that that 10–30% of alternative splicing events are tissue specific (41), suggesting function.…”

Section: Discussionmentioning

confidence: 99%

Stochastic noise in splicing machinery

Melamud

Moult

2009

Nucleic Acids Research

156

152

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The number of known alternative human isoforms has been increasing steadily with the amount of available transcription data. To date, over 100 000 isoforms have been detected in EST libraries, and at least 75% of human genes have at least one alternative isoform. In this paper, we propose that most alternative splicing events are the result of noise in the splicing process. We show that the number of isoforms and their abundance can be predicted by a simple stochastic noise model that takes into account two factors: the number of introns in a gene and the expression level of a gene. The results strongly support the hypothesis that most alternative splicing is a consequence of stochastic noise in the splicing machinery, and has no functional significance. The results are also consistent with error rates tuned to ensure that an adequate level of functional product is produced and to reduce the toxic effect of accumulation of misfolding proteins. Based on simulation of sampling of virtual cDNA libraries, we estimate that error rates range from 1 to 10% depending on the number of introns and the expression level of a gene.

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“…Analysis of the post-transcriptional regulation of the Mid1 mRNA has shown that alternative use of different transcription start sites, alternative splicing, and the existence of different polyadenylation signal results in a wide variety of Mid1 isoforms (Landry and Mager, 2002; Winter et al, 2004). Less is known, however, about the transcriptional mechanisms that regulate Mid1 expression.…”

Section: Discussionmentioning

confidence: 99%

Reduced Mid1 Expression and Delayed Neuromotor Development in daDREAM Transgenic Mice

Dierssen¹,

Fedrizzi²,

Gómez‐Villafuertes³

et al. 2012

Front. Mol. Neurosci.

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Downstream regulatory element antagonist modulator (DREAM) is a Ca2+-binding protein that binds DNA and represses transcription in a Ca2+-dependent manner. Previous work has shown a role for DREAM in cerebellar function regulating the expression of the sodium/calcium exchanger 3 (NCX3) in cerebellar granular neurons to control Ca2+ homeostasis and survival of these neurons. To achieve a global view of the genes regulated by DREAM in the cerebellum, we performed a genome-wide analysis in transgenic cerebellum expressing a Ca2+-insensitive/CREB-independent dominant active mutant DREAM (daDREAM). Here we show that DREAM regulates the expression of the midline 1 (Mid1) gene early after birth. As a consequence, daDREAM mice exhibit a significant shortening of the rostro-caudal axis of the cerebellum and a delay in neuromotor development early after birth. Our results indicate a role for DREAM in cerebellar function.

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Regulation of the MID1 protein function is fine-tuned by a complex pattern of alternative splicing

Cited by 25 publications

References 25 publications

A pronounced evolutionary shift of the pseudoautosomal region boundary in house mice

A pronounced evolutionary shift of the pseudoautosomal region boundary in house mice

Stochastic noise in splicing machinery

Reduced Mid1 Expression and Delayed Neuromotor Development in daDREAM Transgenic Mice

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