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

Molecular psychiatry 2022 Nov

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The precise development of the neocortex is a prerequisite for higher cognitive and associative functions. Despite numerous advances that have been made in understanding neuronal differentiation and cortex development, our knowledge regarding the impact of specific genes associated with neurodevelopmental disorders on these processes is still limited. Here, we show that Taok2, which is encoded in humans within the autism spectrum disorder (ASD) susceptibility locus 16p11.2, is essential for neuronal migration. Overexpression of de novo mutations or rare variants from ASD patients disrupts neuronal migration in an isoform-specific manner. The mutated TAOK2α variants but not the TAOK2β variants impaired neuronal migration. Moreover, the TAOK2α isoform colocalizes with microtubules. Consequently, neurons lacking Taok2 have unstable microtubules with reduced levels of acetylated tubulin and phosphorylated JNK1. Mice lacking Taok2 develop gross cortical and cortex layering abnormalities. Moreover, acute Taok2 downregulation or Taok2 knockout delayed the migration of upper-layer cortical neurons in mice, and the expression of a constitutively active form of JNK1 rescued these neuronal migration defects. Finally, we report that the brains of the Taok2 KO and 16p11.2 del Het mouse models show striking anatomical similarities and that the heterozygous 16p11.2 microdeletion mouse model displayed reduced levels of phosphorylated JNK1 and neuronal migration deficits, which were ameliorated upon the introduction of TAOK2α in cortical neurons and in the developing cortex of those mice. These results delineate the critical role of TAOK2 in cortical development and its contribution to neurodevelopmental disorders, including ASD. © 2022. The Author(s).

Citation

Robin Scharrenberg, Melanie Richter, Ole Johanns, Durga Praveen Meka, Tabitha Rücker, Nadeem Murtaza, Zsuzsa Lindenmaier, Jacob Ellegood, Anne Naumann, Bing Zhao, Birgit Schwanke, Jan Sedlacik, Jens Fiehler, Ileana L Hanganu-Opatz, Jason P Lerch, Karun K Singh, Froylan Calderon de Anda. TAOK2 rescues autism-linked developmental deficits in a 16p11.2 microdeletion mouse model. Molecular psychiatry. 2022 Nov;27(11):4707-4721