Lineage-specific splicing regulation of MAPT gene in the primate brain.
Cell Genom
; 4(6): 100563, 2024 Jun 12.
Article
em En
| MEDLINE
| ID: mdl-38772368
ABSTRACT
Divergence of precursor messenger RNA (pre-mRNA) alternative splicing (AS) is widespread in mammals, including primates, but the underlying mechanisms and functional impact are poorly understood. Here, we modeled cassette exon inclusion in primate brains as a quantitative trait and identified 1,170 (â¼3%) exons with lineage-specific splicing shifts under stabilizing selection. Among them, microtubule-associated protein tau (MAPT) exons 2 and 10 underwent anticorrelated, two-step evolutionary shifts in the catarrhine and hominoid lineages, leading to their present inclusion levels in humans. The developmental-stage-specific divergence of exon 10 splicing, whose dysregulation can cause frontotemporal lobar degeneration (FTLD), is mediated by divergent distal intronic MBNL-binding sites. Competitive binding of these sites by CRISPR-dCas13d/gRNAs effectively reduces exon 10 inclusion, potentially providing a therapeutically compatible approach to modulate tau isoform expression. Our data suggest adaptation of MAPT function and, more generally, a role for AS in the evolutionary expansion of the primate brain.
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Base de dados:
MEDLINE
Assunto principal:
Encéfalo
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Éxons
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Proteínas tau
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Processamento Alternativo
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article