[Seminar] A neuron-specific microexon implicated in X-linked dystonia-parkinsonism (XDP) controls subcellular localization of TAF1 by Dr. Jill R. Crittenden
Mutations in the RNA polymerase subunit TAF1 can cause two different diseases: X-linked dystonia parkinsonism (XDP/DYT3) and X-linked intellectual disability syndrome (MRXS33). XDP is an adult onset disorder characterized by neurodegeneration of the striatum, generalized dystonia and parkinsonism. XDP is caused by an insertion of retrotransposon SVA (SINE-VNTR-Alu) upstream of a neuron-specific TAF1 microexon. The causative mutations identified so far for MRXS33 are all located 5’ of the SVA insertion site and cause growth retardation, facial dysmorphology, psychomotor symptoms, and intellectual disability.
To better understand the differences between the TAF1 isoforms that cause XDP and MRXS33, we directly compared mRNA and protein expression patterns of TAF1 isoforms that include or exclude the neuron-specific microexon. We used BaseScope™ probes and antibodies to detect inclusion/exclusion of the microexon, which is only six basepairs long and encodes the amino acids alanine and lysine. These reagents showed that the TAF1 microexon is neuron-specific and overlaps in expression with the microexon splicing factor nSR100/SRRM4. By contrast, TAF1 that excludes the microexon is expressed ubiquitously, as previously shown by other methods. Importantly, double-labeling in brains from humans and mice showed that TAF1 isoforms that include or exclude the microexon are localized to separate sites within the nucleus.
The restriction of TAF1 microexon expression to post-mitotic neurons is consistent with the neuronal phenotype of XDP, relative to the more widespread symptoms of MRXS33. The striking difference in TAF1 subnuclear localization upon inclusion of the microexon suggests that symptom differences are also related to a unique transcriptional function of neuronal TAF1. Thousands of putative microexons have now been identified and the validation of reagents to distinguish their localization in situ will expedite the understanding of their significance in disease.
Funding: Collaborative Center for X-linked Dystonia Parkinsonism, The James and Pat Poitras Research Fund, and The Saks Kavanaugh Foundation.
2005-current Massachusetts Institute of Technology, Cambridge, MA
Research Scientist with Prof. David E. Housman and Institute Prof. Ann M. Graybiel
Development and characterization of mouse models of movement and psychiatric disorders.
2000-2005 Massachusetts Institute of Technology, Cambridge, MA
Postdoctoral Associate and Fellow with Profs. Ann M. Graybiel and David E. Housman
1998-2000 Baylor College of Medicine, Houston, TX
Postdoctoral Associate with Prof. Ronald L. Davis
AWARDS, FELLOWSHIPS and GRANTS
2018-2019 CCXDP Exploratory Pilot Grant, PI
2017-2019 CCXDP Center Grant, PI
2017-2019 Bumpus Innovation Award, PI
2016 Travel Award for the Dopamine 2016 Conference
2015 XDP Center Grant, Co-PI
2014 Travel Award for the Basal Ganglia Gordon Research Conference
2013 Massachusetts Neuroscience Consortium Grant, Co-PI
2010 Travel Award for the 10th International Basal Ganglia Society Meeting (IBAGSX)
2009 Osaka University Global Center of Excellence Travel Award
2008-2010 Michael J Fox Foundation for Parkinson’s Research, Target Validation Grant, Co-PI