Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development
Morandell J, Schwarz L, Basilico B, Tasciyan S, Dimchev G, Nicolas A, Sommer C, Kreuzinger C, Dotter C, Knaus L, Dobler Z, Cacci E, Schur F, Danzl J, Novarino G (2021) Nature Communications 12, 3058 doi.org/10.1038/s41467-021-23123-x
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Abstract:
De novo loss of function mutations in the ubiquitin ligase-encoding gene Cullin3 (CUL3) lead to autism spectrum disorder (ASD). In mouse, constitutive Cul3 haploinsufficiency leads to motor coordination deficits as well as ASD-relevant social and cognitive impairments. However, induction of Cul3 haploinsufficiency later in life does not lead to ASD-relevant behaviors, pointing to an important role of Cul3 during a critical developmental window. Here we show that Cul3 is essential to regulate neuronal migration and, therefore, constitutive Cul3 heterozygous mutant mice display cortical lamination abnormalities. At the molecular level, we found that Cul3 controls neuronal migration by tightly regulating the amount of Plastin3 (Pls3), a previously unrecognized player of neural migration. Furthermore, we found that Pls3 cell-autonomously regulates cell migration by regulating actin cytoskeleton organization, and its levels are inversely proportional to neural migration speed. Finally, we provide evidence that cellular phenotypes associated with autism-linked gene haploinsufficiency can be rescued by transcriptional activation of the intact allele in vitro, offering a proof of concept for a potential therapeutic approach for ASDs.FAB RESEARCH COMMENT:
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