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Research Articles, Cellular/Molecular

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 and Elena Battaglioli
Journal of Neuroscience 4 May 2022, 42 (18) 3689-3703; DOI: https://doi.org/10.1523/JNEUROSCI.1782-21.2022
Chiara Forastieri
1Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Segrate, 20090, Italy
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Maria Italia
1Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Segrate, 20090, Italy
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  • ORCID record for Maria Italia
Emanuela Toffolo
1Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Segrate, 20090, Italy
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Elena Romito
1Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Segrate, 20090, Italy
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Maria Paola Bonasoni
2ASMN Santa Maria Nuova, Reggio Emilia, 42123, Italy
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Valeria Ranzani
3Istituto Nazionale di Genetica Molecolare “Romeo ed Enrica Invernizzi,” Milano, 20122, Italy
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Beatrice Bodega
3Istituto Nazionale di Genetica Molecolare “Romeo ed Enrica Invernizzi,” Milano, 20122, Italy
4Department of Biosciences, Università degli Studi di Milano, Milano, 20133, Italy
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Francesco Rusconi
1Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Segrate, 20090, Italy
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Elena Battaglioli
1Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Segrate, 20090, Italy
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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.

SIGNIFICANCE STATEMENT To be better understood, anxiety and depression need large human genetics studies aimed at further resolving the often ambiguous, aberrant neuronal pathomechanisms that impact corticolimbic circuitry physiology. Several genetic associations of the alternative splicing regulator RbFOX1 with psychiatric conditions suggest homeostatic unbalance as a neuronal signature of psychopathology. Here we move a step forward, characterizing a disease-relevant higher primates-specific pathway by which RbFOX1 acquires the ability to regulate neuronal levels of Lysine Specific Demethylase 1, an epigenetic modulator of environmental stress response. Thus, two brain-enriched enzymes, independently shown to homeostatically protect neurons with a clear readout in terms of emotional behavior in lower mammals, establish in higher primates and humans a new functional cooperation enhancing the complexity of environmental adaptation and stress vulnerability.

  • evolution
  • lysine specific demethylase 1
  • major depressive disorder
  • non-sense-mediated decay
  • psychiatric disorders
  • RNA-binding Fox homolog 1

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The Journal of Neuroscience: 42 (18)
Journal of Neuroscience
Vol. 42, Issue 18
4 May 2022
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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
Journal of Neuroscience 4 May 2022, 42 (18) 3689-3703; DOI: 10.1523/JNEUROSCI.1782-21.2022

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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
Journal of Neuroscience 4 May 2022, 42 (18) 3689-3703; DOI: 10.1523/JNEUROSCI.1782-21.2022
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Keywords

  • evolution
  • lysine specific demethylase 1
  • major depressive disorder
  • non-sense-mediated decay
  • psychiatric disorders
  • RNA-binding Fox homolog 1

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