Crombie, Elisa M;
Korecki, Andrea J;
Cleverley, Karen;
Adair, Bethany A;
Cunningham, Thomas J;
Lee, Weaverly Colleen;
Lengyell, Tess C;
... Simpson, Elizabeth M; + view all
(2024)
Taf1 knockout is lethal in embryonic male mice and heterozygous females show weight and movement disorders.
Disease Models & Mechanisms
, 17
(7)
, Article dmm050741. 10.1242/dmm.050741.
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Abstract
The TATA box-binding protein-associated factor 1 (TAF1) is a ubiquitously expressed protein and the largest subunit of the basal transcription factor TFIID, which plays a key role in initiation of RNA polymerase II-dependent transcription. TAF1 missense variants in human males cause X-linked intellectual disability, a neurodevelopmental disorder, and TAF1 is dysregulated in X-linked dystonia–parkinsonism, a neurodegenerative disorder. However, this field has lacked a genetic mouse model of TAF1 disease to explore its mechanism in mammals and treatments. Here, we generated and validated a conditional cre-lox allele and the first ubiquitous Taf1 knockout mouse. We discovered that Taf1 deletion in male mice was embryonically lethal, which may explain why no null variants have been identified in humans. In the brains of Taf1 heterozygous female mice, no differences were found in gross structure, overall expression and protein localisation, suggesting extreme skewed X inactivation towards the non-mutant chromosome. Nevertheless, these female mice exhibited a significant increase in weight, weight with age, and reduced movement, suggesting that a small subset of neurons was negatively impacted by Taf1 loss. Finally, this new mouse model may be a future platform for the development of TAF1 disease therapeutics.
| Type: | Article |
|---|---|
| Title: | Taf1 knockout is lethal in embryonic male mice and heterozygous females show weight and movement disorders |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1242/dmm.050741 |
| Publisher version: | https://doi.org/10.1242/dmm.050741 |
| Language: | English |
| Additional information: | Copyright © 2024. Published by The Company of Biologists Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. |
| Keywords: | TATA box-binding protein-associated factor 1, X-linked dystonia–parkinsonism, Male lethality, X-linked intellectual disability, X inactivation, Genetic mouse model, Transcription initiation complex |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Institute of Prion Diseases UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Institute of Prion Diseases > MRC Prion Unit at UCL |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10201269 |
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