<i>Cul3</i> Regulates Cytoskeleton Protein Homeostasis and Cell Migration During a Critical Window of Brain Development

• DOI: 10.2139/ssrn.3535873
• Publication Date: 2020-02-13T06:31:09Z
• 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 Danzl; Gaia Novarino
• Keywords: Male; 0301 basic medicine; Heterozygote; Autism Spectrum Disorder; Science; Haploinsufficiency; Microtubules; Nervous System; Article; Mice; 03 medical and health sciences; Prosencephalon; Cell Movement; Genes, Regulator; Animals; Homeostasis; brain development; migration; neural stem cells; autism spectrum disorder; Autistic Disorder; Cytoskeleton; Mice, Knockout; 0303 health sciences; Q; Brain; Cullin Proteins; Mice, Inbred C57BL; Mutation; Female

AbstractDe novoloss of function mutations in the ubiquitin ligase-encoding geneCullin3(CUL3)lead to autism spectrum disorder (ASD). Here, we usedCul3mouse models to evaluate the consequences ofCul3mutationsin vivo.Our results show thatCul3haploinsufficient mice exhibit deficits in motor coordination as well as ASD-relevant social and cognitive impairments.Cul3mutant brain displays cortical lamination abnormalities due to defective neuronal migration and reduced numbers of excitatory and inhibitory neurons. In line with the observed abnormal columnar organization,Cul3haploinsufficiency is associated with decreased spontaneous excitatory and inhibitory activity in the cortex. At the molecular level, employing a quantitative proteomic approach, we show thatCul3regulates cytoskeletal and adhesion protein abundance in mouse embryos. Abnormal regulation of cytoskeletal proteins inCul3mutant neuronal cells results in atypical organization of the actin mesh at the cell leading edge, likely causing the observed migration deficits. In contrast to these important functions early in development,Cul3deficiency appears less relevant at adult stages. In fact, induction ofCul3haploinsufficiency in adult mice does not result in the behavioral defects observed in constitutiveCul3haploinsufficient animals. Taken together, our data indicate thatCul3has a critical role in the regulation of cytoskeletal proteins and neuronal migration and that ASD-associated defects and behavioral abnormalities are primarily due toCul3functions at early developmental stages.