TAOK2 rescues autism-linked developmental deficits in a 16p11.2 microdeletion mouse model

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• Neocortex development is vital for cognitive functions.
• Understanding gene impacts on neurodevelopmental disorders is limited.
• Taok2 is located within the autism spectrum disorder (ASD) susceptibility locus 16p11.2.

Purpose of the Study:

• Investigate the role of Taok2 in neuronal migration and cortex development.
• Determine the impact of ASD-associated Taok2 variants on neuronal migration.
• Elucidate the molecular mechanisms underlying Taok2's function.

Main Methods:

• Overexpression of Taok2 variants in neuronal cultures.
• Analysis of microtubule stability and JNK1 phosphorylation.
• Generation and analysis of Taok2 knockout and 16p11.2 deletion mouse models.
• Assessment of cortical layering and neuronal migration in mice.

Main Results:

• Taok2 is essential for neuronal migration; its absence causes cortical abnormalities.
• ASD-associated TAOK2α variants, but not TAOK2β, impair neuronal migration.
• Taok2 influences microtubule stability and JNK1 phosphorylation.
• Taok2 knockout and 16p11.2 deletion models exhibit similar brain abnormalities.
• Restoring TAOK2α ameliorates migration deficits in 16p11.2 deletion models.

Conclusions:

• Taok2 plays a critical role in neocortical development and neuronal migration.
• Disruption of Taok2 function contributes to neurodevelopmental disorders like ASD.
• The TAOK2α isoform is specifically involved in regulating neuronal migration via microtubule dynamics and JNK1 signaling.