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.

Evolution increases primates brain complexity extending RbFOX1 splicing activity to LSD1 modulation / C. Forastieri, M. Italia, E. Toffolo, E. Romito, M. Bonasoni, V. Ranzani, B. Bodega, F.S. Rusconi, E. Battaglioli. - In: THE JOURNAL OF NEUROSCIENCE. - ISSN 1529-2401. - 42:18(2022 May 04), pp. 3689-3703. [10.1523/JNEUROSCI.1782-21.2022]

Evolution increases primates brain complexity extending RbFOX1 splicing activity to LSD1 modulation

C. Forastieri
Primo
;
M. Italia
Secondo
;
E. Toffolo;E. Romito;B. Bodega;F.S. Rusconi
Penultimo
;
E. Battaglioli
Ultimo
2022

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.
evolution; lysine specific demethylase 1; major depressive disorder; non-sense-mediated decay; psychiatric disorders; RNA-binding Fox homolog 1;
Settore BIO/13 - Biologia Applicata
   Role of LSD1 in aging-dependent epigenetic drift leading to frailty-associated mood disorders
   FONDAZIONE CARIPLO
   2016-0908

   Piano di Sostegno alla Ricerca 2015-2017 - Linea 2 "Dotazione annuale per attività istituzionali" (anno 2019)
   UNIVERSITA' DEGLI STUDI DI MILANO

   Study of the Biological Role of LSD1/KDM1A Splicing Variants in Human Embryonic Stem Cells and Early Development
   KING ABDULLAH UNIVERSITY OF SCIENCE AND TECHNOLOGY
   OSR-2019-CRG8-4012.3
4-mag-2022
mar-2022
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/919550
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