Biomedical subjects

Marianne Malartre

Publications and source records attributed to Marianne Malartre.

3 recordsLinked to original sources

PubMed2006

Xenopus embryos lacking specific isoforms of the corepressor SMRT develop abnormal heads.

The corepressor SMRT acts on a range of transcription factors, including the retinoid and thyroid hormone nuclear receptors. The carboxy-terminal region of SMRT contains CoRNR box motifs that mediate these interactions. We have shown, in Xenopus, that SMRT can exist as isoforms containing either two or three CoRNR boxes depending on the alternative splicing of exon 37b. The number of SMRT transcript isoforms expressed increases during development until all sixteen possible isoforms are identified in the swimming tadpole. To eliminate specific SMRT isoforms, we have developed a process that uses an antisense morpholino oligonucleotide in Xenopus to dictate the outcome of alternative splicing at a defined exon and used this to inhibit the formation of transcripts containing exon 37b. These embryos are therefore limited to the expression of SMRT isoforms that contain two rather than three CoRNR boxes. Analysis of responsive genes in these embryos shows that targets of thyroid hormone, but not retinoid signaling are affected by the elimination of exon 37b. Morpholino-injected embryos have swimming abnormalities and develop altered head morphology, an expanded olfactory epithelium and disorganized peripheral axons. These experiments indicate a critical role for the alternative splicing of SMRT in development.

Alternative Splicing↗

PubMed2005

SMRT has tissue-specific isoform profiles that include a form containing one CoRNR box.

SMRT acts as a corepressor for a range of transcription factors. The amino-terminal part of the protein includes domains that mainly mediate transcriptional repression whilst the carboxy-terminal part includes domains that interact with nuclear receptors using up to three motifs called CoRNR boxes. The region of the SMRT primary transcript encoding the interaction domains is subject to alternative splicing that varies the inclusion of the third CoRNR box. The profile in mice includes an abundant, novel SMRT isoform that possesses just one CoRNR box. Mouse tissues therefore express SMRT isoforms containing one, two or three CoRNR boxes. In frogs, the SMRT isoform profile is tissue-specific. The mouse also shows distinct profiles generated by differential expression levels of the SMRT transcript isoforms. The formation of multiple SMRT isoforms and their tissue-specific regulation indicates a mechanism, whereby cells can define the repertoire of transcription factors regulated by SMRT.

Alternative Splicing↗

PubMed2004

Alternative splicing generates multiple SMRT transcripts encoding conserved repressor domains linked to variable transcription factor interaction domains.

Silencing mediator for retinoid and thyroid hormone receptor (SMRT) and nuclear receptor corepressor protein (NCoR) are corepressors that interact with a range of transcription factors. They both consist of N-terminal repressor domains that associate with histone deacetylases and C-terminal interaction domains (IDs) that contain CoRNR box motifs. These motifs mediate the interaction between corepressors and nuclear receptors (NRs), such as the retinoid and thyroid hormone receptors. However, whilst NCoR produces a single transcript during Xenopus development, xSMRT is subject to alternative splicing at four sites in the 3' part of the transcript, the region encoding the C-terminal IDs. Although this provides the potential to produce 16 different transcripts, only five isoforms are found in early embryos. The sites of alternative splicing predict that the resultant isoforms will differ in their ability to interact with NRs, as one site varies the number of CoRNR boxes, the second site changes the sequence flanking CoRNR box-1 and the other sites delete amino acid residues between CoRNR boxes 1 and 2 and so alter the critical spacing between these motifs. SMRT and NCoR therefore represent paralogues in which one form, SMRT, has evolved the ability to generate multiple isoforms whereas the other, NCoR, is invariant in Xenopus development.

Alternative Splicing↗