Evolution Increases Primates Brain Complexity Extending RbFOX1 Splicing Activity to LSD1 Modulation

Chiara Forastieri, Maria Italia, Emanuela Toffolo, Elena Romito, Maria Paola Bonasoni, Valeria Ranzani, Beatrice Bodega, Francesco Rusconi, Elena Battaglioli

Research output: Contribution to journalArticlepeer-review

Abstract

Recent branching (100 MYA) of the mammalian evolutionary tree has enhanced brain complexity and functions at the putative cost of increased emotional circuitry vulnerability. Thus, to better understand psychopathology, a burden for the modern society, novel approaches should exploit evolutionary aspects of psychiatric-relevant molecular pathways. A handful of genes is nowadays tightly associated to psychiatric disorders. Among them, neuronal-enriched RbFOX1 modifies the activity of synaptic regulators in response to neuronal activity, keeping excitability within healthy domains. We here dissect a higher primates-restricted interaction between RbFOX1 and the transcriptional corepressor Lysine Specific Demethylase 1 (LSD1/KDM1A). A single nucleotide variation (AA to AG) in LSD1 gene appeared in higher primates and humans, endowing RbFOX1 with the ability to promote the alternative usage of a novel 3′ AG splice site, which extends LSD1 exon E9 in the upstream intron (E9-long). Exon E9-long regulates LSD1 levels by Nonsense-Mediated mRNA Decay. As reintroduction of the archaic LSD1 variant (AA) abolishes E9-long splicing, the novel 3′ AG splice site is necessary for RbFOX1 to control LSD1 levels. LSD1 is a homeostatic immediate early genes (IEGs) regulator playing a relevant part in environmental stress-response. In primates and humans, inclusion of LSD1 as RbFOX1 target provides RbFOX1 with the additional ability to regulate the IEGs. These data, together with extensive RbFOX1 involvement in psychiatric disorders and its stress-dependent regulation in male mice, suggest the RbFOX1-LSD1-IEGs axis as an evolutionary recent psychiatric-relevant pathway. Notably, outside the nervous system, RbFOX2-dependent LSD1 modulation could be a candidate deregulated mechanism in cancer.
Original languageEnglish (US)
Pages (from-to)JN-RM-1782-21
Number of pages1
JournalThe Journal of Neuroscience
DOIs
StatePublished - Mar 29 2022
Externally publishedYes

Bibliographical note

KAUST Repository Item: Exported on 2022-04-05
Acknowledged KAUST grant number(s): CRG 2018
Acknowledgements: This work was supported by CARIPLO Foundation Grant 2016-0908 and KAUST CRG 2018 to E.B. and PSR_2019 to F.R. We thank Leda Paganini for the initial contribution to the work; Graziano Rocchi for providing nonprimates and primate cell lines; and Marco Venturin for postmortem human cerebellar and hippocampal samples.
This publication acknowledges KAUST support, but has no KAUST affiliated authors.

ASJC Scopus subject areas

  • Neuroscience(all)

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