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Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development

Jasmin Morandell, Lena A. Schwarz, Bernadette Basilico, Saren Tasciyan, Armel Nicolas, Christoph Sommer, Caroline Kreuzinger, Christoph P. Dotter, Lisa S. Knaus, Zoe Dobler, Emanuele Cacci, Johann G. Danzl, View ORCID ProfileGaia Novarino
doi: https://doi.org/10.1101/2020.01.10.902064
Jasmin Morandell
1Institute of Science and Technology (IST) Austria, Klosterneuburg, Austria
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Lena A. Schwarz
1Institute of Science and Technology (IST) Austria, Klosterneuburg, Austria
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Bernadette Basilico
1Institute of Science and Technology (IST) Austria, Klosterneuburg, Austria
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Saren Tasciyan
1Institute of Science and Technology (IST) Austria, Klosterneuburg, Austria
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Armel Nicolas
1Institute of Science and Technology (IST) Austria, Klosterneuburg, Austria
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Christoph Sommer
1Institute of Science and Technology (IST) Austria, Klosterneuburg, Austria
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Caroline Kreuzinger
1Institute of Science and Technology (IST) Austria, Klosterneuburg, Austria
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Christoph P. Dotter
1Institute of Science and Technology (IST) Austria, Klosterneuburg, Austria
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Lisa S. Knaus
1Institute of Science and Technology (IST) Austria, Klosterneuburg, Austria
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Zoe Dobler
1Institute of Science and Technology (IST) Austria, Klosterneuburg, Austria
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Emanuele Cacci
2Department of Biology and Biotechnology “Charles Darwin”, Sapienza, University of Rome
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Johann G. Danzl
1Institute of Science and Technology (IST) Austria, Klosterneuburg, Austria
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Gaia Novarino
1Institute of Science and Technology (IST) Austria, Klosterneuburg, Austria
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  • ORCID record for Gaia Novarino
  • For correspondence: gnovarino@ist.ac.at
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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). Here, we used Cul3 mouse models to evaluate the consequences of Cul3 mutations in vivo. Our results show that Cul3 haploinsufficient mice exhibit deficits in motor coordination as well as ASD-relevant social and cognitive impairments. Cul3 mutant 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, Cul3 haploinsufficiency is associated with decreased spontaneous excitatory and inhibitory activity in the cortex. At the molecular level, employing a quantitative proteomic approach, we show that Cul3 regulates cytoskeletal and adhesion protein abundance in mouse embryos. Abnormal regulation of cytoskeletal proteins in Cul3 mutant 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, Cul3 deficiency appears less relevant at adult stages. In fact, induction of Cul3 haploinsufficiency in adult mice does not result in the behavioral defects observed in constitutive Cul3 haploinsufficient animals. Taken together, our data indicate that Cul3 has a critical role in the regulation of cytoskeletal proteins and neuronal migration and that ASD-associated defects and behavioral abnormalities are primarily due to Cul3 functions at early developmental stages.

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Posted January 11, 2020.
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Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development
Jasmin Morandell, Lena A. Schwarz, Bernadette Basilico, Saren Tasciyan, Armel Nicolas, Christoph Sommer, Caroline Kreuzinger, Christoph P. Dotter, Lisa S. Knaus, Zoe Dobler, Emanuele Cacci, Johann G. Danzl, Gaia Novarino
bioRxiv 2020.01.10.902064; doi: https://doi.org/10.1101/2020.01.10.902064
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Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development
Jasmin Morandell, Lena A. Schwarz, Bernadette Basilico, Saren Tasciyan, Armel Nicolas, Christoph Sommer, Caroline Kreuzinger, Christoph P. Dotter, Lisa S. Knaus, Zoe Dobler, Emanuele Cacci, Johann G. Danzl, Gaia Novarino
bioRxiv 2020.01.10.902064; doi: https://doi.org/10.1101/2020.01.10.902064

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