Cul3 Regulates Cytoskeleton Protein Homeostasis and Cell Migration During a Critical Window of Brain Development

Overview

Journal Nat Commun

Specialty Biology

Date 2021 May 25

PMID 34031387

Citations 15

Authors

Jasmin Morandell

Lena A Schwarz

Bernadette Basilico

Saren Tasciyan

Georgi Dimchev

Armel Nicolas

Christoph Sommer

Caroline Kreuzinger

Christoph P Dotter

Lisa S Knaus

Zoe Dobler

Emanuele Cacci

Florian K M Schur

Johann G Danzl

Gaia Novarino

Affiliations

Soon will be listed here.

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.

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