Intron detention tightly regulates the stemness/differentiation switch in the adult neurogenic niche

Ainara González-Iglesias, Aida Arcas, Ana Domingo-Muelas, Estefania Mancini, Joan Galcerán, Juan Valcárcel, Isabel Fariñas and M. Angela Nieto ()
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Ainara González-Iglesias: Instituto de Neurociencias (CSIC-UMH)
Aida Arcas: Instituto de Neurociencias (CSIC-UMH)
Ana Domingo-Muelas: Universidad de Valencia
Estefania Mancini: The Barcelona Institute of Science and Technology
Joan Galcerán: Instituto de Neurociencias (CSIC-UMH)
Juan Valcárcel: The Barcelona Institute of Science and Technology
Isabel Fariñas: Universidad de Valencia
M. Angela Nieto: Instituto de Neurociencias (CSIC-UMH)

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract The adult mammalian brain retains some capacity to replenish neurons and glia, holding promise for brain regeneration. Thus, understanding the mechanisms controlling adult neural stem cell (NSC) differentiation is crucial. Paradoxically, adult NSCs in the subependymal zone transcribe genes associated with both multipotency maintenance and neural differentiation, but the mechanism that prevents conflicts in fate decisions due to these opposing transcriptional programmes is unknown. Here we describe intron detention as such control mechanism. In NSCs, while multiple mRNAs from stemness genes are spliced and exported to the cytoplasm, transcripts from differentiation genes remain unspliced and detained in the nucleus, and the opposite is true under neural differentiation conditions. We also show that m6A methylation is the mechanism that releases intron detention and triggers nuclear export, enabling rapid and synchronized responses. m6A RNA methylation operates as an on/off switch for transcripts with antagonistic functions, tightly controlling the timing of NSCs commitment to differentiation.

Date: 2024
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DOI: 10.1038/s41467-024-47092-z

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