RBMX functional retrocopy safeguards brain development in a species-dependent context.

Area of Science:

• Genomics
• Neuroscience
• Evolutionary Biology

Background:

• Retrotransposition generates numerous intronless gene copies in mammalian genomes.
• The role of these retrocopies in brain development and evolution is understudied.
• RBMX, an X-linked RNA-binding protein, has similar retrocopies (RBMXL1) suggesting functional importance.

Purpose of the Study:

• To investigate the functional redundancy between RBMX and its retrocopy RBMXL1 in brain development.
• To understand the mechanisms by which RBMX variants cause neurodevelopmental disorders.
• To explore the role of retrocopies in mammalian brain evolution and robustness.

Main Methods:

• Exome sequencing and GeneMatcher to identify individuals with RBMX variants.
• Transcriptomic profiling, protein-protein, and protein-RNA interaction studies in human cells and mouse cortices.
• Mouse genetics to study RBMX function and RBMXL1 compensation in corticogenesis.

Main Results:

• Hemizygous RBMX variants cause neurodevelopmental disorders with intellectual disability and malformations.
• RBMX variants disrupt cortical development via loss-of-function and gain-of-function mechanisms.
• Rbmx-deficient mice show mild cortical abnormalities, indicating functional compensation by RBMXL1.

Conclusions:

• RBMX and RBMXL1 share protein and RNA partners, acting redundantly in brain development.
• RBMXL1 buffers the effects of RBMX deficiency, contributing to neurodevelopmental robustness.
• Functional retrocopies can facilitate mammalian brain evolution and diversify gene function.