New article in Nature Communications
Our latest research is now published in the journal Nature Communications and is accessible as an open access manuscript!
Loss of one allele of NUAK1 disrupts brain development in the mouse. One of the main phenotype is an enlargment of the lateral ventricles (visible on the right) with a corresponding thinning of the cortex.
The etiology of neurodevelopmental diseases such as autistic spectrum disorders (ASD), schizophrenia, cognitive deficit or epilepsy involves a complex interaction between genes and environment. Recent studies uncovered numerous de novo mutations (ie. mutations found in affected patients but not in parents and siblings, as opposed to germline mutations) in patients affected by neurodevelopmental disorders. Yet the biological significance of such mutations and the relevance for the pathology is in most case unknown.
Our work focused on de novo mutations in Nuak1, an AMPK related kinase involved in cortical development (1) has been identified as a candidate gene for ASD (2,3). We tested whether Nuak1 is haploinsufficient for cortical development as well as the functional consequences of a ASD-associated Nuak1 mutation in in vitro and mouse models.
In this study we demonstrate that the inactivation of one allele of Nuak1 in the mouse leads to a complex phenotype including neuroanatomical defects including growth retardation, enlargment of the lateral ventricles and decreased terminal axon branching of cortico-cortical projections. Behavioral testing in the mouse revealed a combination of abnormal traits ranging from defective spatial memory consolidation, defects in social novelty (but not social preference) and abnormal sensorimotor gating. Finally, using a gene-replacement strategy we characterized the functional consequence of Nuak1 rare de novo mutation identified in ASD patients.
Overall, our results indicate that Nuak1 is haploinsufficient regarding its role in the development of cortical connectivity and support the hypothesis that loss-of-function mutations in Nuak1 participates in the etiology of neurodevelopmental disorders.
(1) see our previous research: Courchet, Lewis et al., Cell 2013
(3) Nuak1 is classified in the SFARI database with a score of 3 (suggestive evidence)
This work was performed at the Institut NeuroMyoGène of Lyon, in collaboration with Franck Polleux’s lab (Columbia University, New York) and Amanda Roberts (the Scripps Research Institute, Californie). Authors are Virginie Courchet, Géraldine Meyer-Dilhet, Peggy Del Carmine and Julien Courchet (INMG), as well as Tommy Lewis, Franck Polleux (Columbia) and Amanda Roberts (Scripps). The work was funded by grants from the NIH, Fondation pour la Recherche Médicale, the Philippe Foundation and ERC Starting Grant.