Journal article
High-resolution temporal and regional mapping of MAPT expression and splicing in human brain development
PloS one, Vol.13(4), pp.e0195771-e0195771
2018
DOI: 10.1371/journal.pone.0195771
PMCID: PMC5892924
PMID: 29634760
Abstract
The microtubule associated protein tau plays a critical role in the pathogenesis of neurodegenerative disease. Recent studies suggest that tau also plays a role in disorders of neuronal connectivity, including epilepsy and post-traumatic stress disorder. Animal studies have shown that the MAPT gene, which codes for the tau protein, undergoes complex pre-mRNA alternative splicing to produce multiple isoforms during brain development. Human data, particularly on temporal and regional variation in tau splicing during development are however lacking. In this study, we present the first detailed examination of the temporal and regional sequence of MAPT alternative splicing in the developing human brain. We used a novel computational analysis of large transcriptomic datasets (total n = 502 patients), quantitative polymerase chain reaction (qPCR) and western blotting to examine tau expression and splicing in post-mortem human fetal, pediatric and adult brains. We found that MAPT exons 2 and 10 undergo abrupt shifts in expression during the perinatal period that are unique in the canonical human microtubule-associated protein family, while exon 3 showed small but significant temporal variation. Tau isoform expression may be a marker of neuronal maturation, temporally correlated with the onset of axonal growth. Immature brain regions such as the ganglionic eminence and rhombic lip had very low tau expression, but within more mature regions, there was little variation in tau expression or splicing. We thus demonstrate an abrupt, evolutionarily conserved shift in tau isoform expression during the human perinatal period that may be due to tau expression in maturing neurons. Alternative splicing of the MAPT pre-mRNA may play a vital role in normal brain development across multiple species and provides a basis for future investigations into the developmental and pathological functions of the tau protein.
Details
- Title: Subtitle
- High-resolution temporal and regional mapping of MAPT expression and splicing in human brain development
- Creators
- Marco M Hefti - Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, United States of AmericaKurt Farrell - Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, United States of AmericaSoongHo Kim - Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, United States of AmericaKathryn R Bowles - Department of Genetics and Genome Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States of AmericaMary E Fowkes - Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of AmericaTowfique Raj - Department of Genetics and Genome Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States of AmericaJohn F Crary - Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
- Resource Type
- Journal article
- Publication Details
- PloS one, Vol.13(4), pp.e0195771-e0195771
- DOI
- 10.1371/journal.pone.0195771
- PMID
- 29634760
- PMCID
- PMC5892924
- NLM abbreviation
- PLoS One
- ISSN
- 1932-6203
- eISSN
- 1932-6203
- Publisher
- Public Library of Science; United States
- Grant note
- R01AG054008 / NIH HHS F32 AG056098 / NIA NIH HHS P50 AG005136 / NIA NIH HHS R01NS095252 / NIH HHS
- Language
- English
- Date published
- 2018
- Academic Unit
- Pathology; Iowa Neuroscience Institute
- Record Identifier
- 9984047863002771
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