article published yes Jasmin Morandell author 4739D480-F248-11E8-B48F-1D18A9856A87 Lena A Schwarz author 29A8453C-F248-11E8-B48F-1D18A9856A87 Bernadette Basilico author 36035796-5ACA-11E9-A75E-7AF2E56974250000-0003-1843-3173 Saren Tasciyan author 4323B49C-F248-11E8-B48F-1D18A9856A870000-0003-1671-393X Georgi A Dimchev author 38C393BE-F248-11E8-B48F-1D18A9856A870000-0001-8370-6161 Armel Nicolas author 2A103192-F248-11E8-B48F-1D18A9856A87 Christoph M Sommer author 4DF26D8C-F248-11E8-B48F-1D18A9856A870000-0003-1216-9105 Caroline Kreuzinger author 382077BA-F248-11E8-B48F-1D18A9856A87 Christoph Dotter author 4C66542E-F248-11E8-B48F-1D18A9856A870000-0002-9033-9096 Lisa Knaus author 3B2ABCF4-F248-11E8-B48F-1D18A9856A87 Zoe Dobler author D23090A2-9057-11EA-883A-A8396FC7A38F Emanuele Cacci author Florian KM Schur author 48AD8942-F248-11E8-B48F-1D18A9856A870000-0003-4790-8078 Johann G Danzl author 42EFD3B6-F248-11E8-B48F-1D18A9856A870000-0001-8559-3973 Gaia Novarino author 3E57A680-F248-11E8-B48F-1D18A9856A870000-0002-7673-7178 GaNo department JoDa department FlSc department MiSi department LifeSc department Bio department ISTplus - Postdoctoral Fellowships project Probing the Reversibility of Autism Spectrum Disorders by Employing in vivo and in vitro Models project Molecular Drug Targets project Stem Cell Modulation in Neural Development and Regeneration/ P07-Neural stem cells in autism and epilepsy project Optical control of synaptic function via adhesion molecules project De novo loss of function mutations in the ubiquitin ligase-encoding gene Cullin3 lead to autism spectrum disorder (ASD). In mouse, constitutive 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. https://research-explorer.ista.ac.at/download/9429/9430/2021_NatureCommunications_Morandell.pdf application/pdfno Springer Nature2021 eng General BiochemistryGenetics and Molecular Biology 2041-1723 00065876990001010.1038/s41467-021-23123-x 121 https://research-explorer.ista.ac.at/record/19557 https://research-explorer.ista.ac.at/record/7800 https://research-explorer.ista.ac.at/record/12401 https://ist.ac.at/en/news/defective-gene-slows-down-brain-cells/ Morandell J, Schwarz LA, Basilico B, Tasciyan S, Dimchev GA, Nicolas A, Sommer CM, Kreuzinger C, Dotter C, Knaus L, Dobler Z, Cacci E, Schur FK, Danzl JG, Novarino G. 2021. Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development. Nature Communications. 12(1), 3058. Morandell, Jasmin, et al. “Cul3 Regulates Cytoskeleton Protein Homeostasis and Cell Migration during a Critical Window of Brain Development.” <i>Nature Communications</i>, vol. 12, no. 1, 3058, Springer Nature, 2021, doi:<a href="https://doi.org/10.1038/s41467-021-23123-x">10.1038/s41467-021-23123-x</a>. Morandell, J., Schwarz, L. A., Basilico, B., Tasciyan, S., Dimchev, G. A., Nicolas, A., … Novarino, G. (2021). Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development. <i>Nature Communications</i>. Springer Nature. <a href="https://doi.org/10.1038/s41467-021-23123-x">https://doi.org/10.1038/s41467-021-23123-x</a> Morandell, Jasmin, Lena A Schwarz, Bernadette Basilico, Saren Tasciyan, Georgi A Dimchev, Armel Nicolas, Christoph M Sommer, et al. “Cul3 Regulates Cytoskeleton Protein Homeostasis and Cell Migration during a Critical Window of Brain Development.” <i>Nature Communications</i>. Springer Nature, 2021. <a href="https://doi.org/10.1038/s41467-021-23123-x">https://doi.org/10.1038/s41467-021-23123-x</a>. J. Morandell, L.A. Schwarz, B. Basilico, S. Tasciyan, G.A. Dimchev, A. Nicolas, C.M. Sommer, C. Kreuzinger, C. Dotter, L. Knaus, Z. Dobler, E. Cacci, F.K. Schur, J.G. Danzl, G. Novarino, Nature Communications 12 (2021). J. Morandell <i>et al.</i>, “Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development,” <i>Nature Communications</i>, vol. 12, no. 1. Springer Nature, 2021. Morandell J, Schwarz LA, Basilico B, et al. Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development. <i>Nature Communications</i>. 2021;12(1). doi:<a href="https://doi.org/10.1038/s41467-021-23123-x">10.1038/s41467-021-23123-x</a> 94292021-05-28T11:49:46Z2026-09-11T22:30:13Z