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

Area of Science:

• Evolutionary biology
• Neuroscience
• Genetics

Background:

• Mammalian brain evolution increased complexity but also emotional vulnerability.
• Psychiatric disorders are linked to specific genes, including the splicing regulator RbFOX1.
• Understanding evolutionary pathways is crucial for novel psychopathology approaches.

Purpose of the Study:

• To investigate a higher primate-specific interaction between RbFOX1 and Lysine Specific Demethylase 1 (LSD1/KDM1A).
• To elucidate the evolutionary role of this interaction in regulating neuronal function and stress response.
• To identify a novel, evolutionarily recent pathway relevant to psychopathology.

Main Methods:

• Analysis of a single nucleotide variation in the LSD1 gene (AA to AG) specific to higher primates.
• Investigation of how this variation enables RbFOX1 to control LSD1 levels via alternative splicing (E9-long) and Nonsense-Mediated mRNA Decay.
• Examination of the RbFOX1-LSD1-IEGs axis in the context of environmental stress response and neuronal homeostasis.

Main Results:

• A primate-specific SNP in LSD1 allows RbFOX1 to promote an E9-long splice variant, regulating LSD1 levels.
• This interaction enables RbFOX1 to control immediate early genes (IEGs), linking it to stress response.
• The RbFOX1-LSD1-IEGs axis is a novel pathway identified in higher primates and humans.

Conclusions:

• The RbFOX1-LSD1-IEGs axis represents an evolutionarily recent pathway contributing to stress vulnerability and psychopathology in higher primates.
• This pathway enhances the complexity of environmental adaptation but increases susceptibility to emotional disorders.
• Dysregulation of LSD1 by RbFOX1 may be relevant in psychiatric conditions and potentially cancer (via RbFOX2).