---
_id: '9429'
abstract:
- lang: eng
  text: 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.
acknowledged_ssus:
- _id: PreCl
acknowledgement: We thank A. Coll Manzano, F. Freeman, M. Ladron de Guevara, and A.
  Ç. Yahya for technical assistance, S. Deixler, A. Lepold, and A. Schlerka for the
  management of our animal colony, as well as M. Schunn and the Preclinical Facility
  team for technical assistance. We thank K. Heesom and her team at the University
  of Bristol Proteomics Facility for the proteomics sample preparation, data generation,
  and analysis support. We thank Y. B. Simon for kindly providing the plasmid for
  lentiviral labeling. Further, we thank M. Sixt for his advice regarding cell migration
  and the fruitful discussions. This work was supported by the ISTPlus postdoctoral
  fellowship (Grant Agreement No. 754411) to B.B., by the European Union’s Horizon
  2020 research and innovation program (ERC) grant 715508 (REVERSEAUTISM), and by
  the Austrian Science Fund (FWF) to G.N. (DK W1232-B24 and SFB F7807-B) and to J.G.D
  (I3600-B27).
article_number: '3058'
article_processing_charge: No
article_type: original
author:
- first_name: Jasmin
  full_name: Morandell, Jasmin
  id: 4739D480-F248-11E8-B48F-1D18A9856A87
  last_name: Morandell
- first_name: Lena A
  full_name: Schwarz, Lena A
  id: 29A8453C-F248-11E8-B48F-1D18A9856A87
  last_name: Schwarz
- first_name: Bernadette
  full_name: Basilico, Bernadette
  id: 36035796-5ACA-11E9-A75E-7AF2E5697425
  last_name: Basilico
  orcid: 0000-0003-1843-3173
- first_name: Saren
  full_name: Tasciyan, Saren
  id: 4323B49C-F248-11E8-B48F-1D18A9856A87
  last_name: Tasciyan
  orcid: 0000-0003-1671-393X
- first_name: Georgi A
  full_name: Dimchev, Georgi A
  id: 38C393BE-F248-11E8-B48F-1D18A9856A87
  last_name: Dimchev
  orcid: 0000-0001-8370-6161
- first_name: Armel
  full_name: Nicolas, Armel
  id: 2A103192-F248-11E8-B48F-1D18A9856A87
  last_name: Nicolas
- first_name: Christoph M
  full_name: Sommer, Christoph M
  id: 4DF26D8C-F248-11E8-B48F-1D18A9856A87
  last_name: Sommer
  orcid: 0000-0003-1216-9105
- first_name: Caroline
  full_name: Kreuzinger, Caroline
  id: 382077BA-F248-11E8-B48F-1D18A9856A87
  last_name: Kreuzinger
- first_name: Christoph
  full_name: Dotter, Christoph
  id: 4C66542E-F248-11E8-B48F-1D18A9856A87
  last_name: Dotter
  orcid: 0000-0002-9033-9096
- first_name: Lisa
  full_name: Knaus, Lisa
  id: 3B2ABCF4-F248-11E8-B48F-1D18A9856A87
  last_name: Knaus
- first_name: Zoe
  full_name: Dobler, Zoe
  id: D23090A2-9057-11EA-883A-A8396FC7A38F
  last_name: Dobler
- first_name: Emanuele
  full_name: Cacci, Emanuele
  last_name: Cacci
- first_name: Florian KM
  full_name: Schur, Florian KM
  id: 48AD8942-F248-11E8-B48F-1D18A9856A87
  last_name: Schur
  orcid: 0000-0003-4790-8078
- first_name: Johann G
  full_name: Danzl, Johann G
  id: 42EFD3B6-F248-11E8-B48F-1D18A9856A87
  last_name: Danzl
  orcid: 0000-0001-8559-3973
- first_name: Gaia
  full_name: Novarino, Gaia
  id: 3E57A680-F248-11E8-B48F-1D18A9856A87
  last_name: Novarino
  orcid: 0000-0002-7673-7178
citation:
  ama: 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>
  apa: 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>
  chicago: 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>.
  ieee: 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.
  ista: 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.
  mla: 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>.
  short: 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).
date_created: 2021-05-28T11:49:46Z
date_published: 2021-05-24T00:00:00Z
date_updated: 2024-09-10T12:04:26Z
day: '24'
ddc:
- '572'
department:
- _id: GaNo
- _id: JoDa
- _id: FlSc
- _id: MiSi
- _id: LifeSc
- _id: Bio
doi: 10.1038/s41467-021-23123-x
ec_funded: 1
external_id:
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status: public
title: Cul3 regulates cytoskeleton protein homeostasis and cell migration during a
  critical window of brain development
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type: journal_article
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year: '2021'
...
---
_id: '8131'
abstract:
- lang: eng
  text: The possibility to generate construct valid animal models enabled the development
    and testing of therapeutic strategies targeting the core features of autism spectrum
    disorders (ASDs). At the same time, these studies highlighted the necessity of
    identifying sensitive developmental time windows for successful therapeutic interventions.
    Animal and human studies also uncovered the possibility to stratify the variety
    of ASDs in molecularly distinct subgroups, potentially facilitating effective
    treatment design. Here, we focus on the molecular pathways emerging as commonly
    affected by mutations in diverse ASD-risk genes, on their role during critical
    windows of brain development and the potential treatments targeting these biological
    processes.
article_processing_charge: Yes (via OA deal)
article_type: original
author:
- first_name: Bernadette
  full_name: Basilico, Bernadette
  id: 36035796-5ACA-11E9-A75E-7AF2E5697425
  last_name: Basilico
  orcid: 0000-0003-1843-3173
- first_name: Jasmin
  full_name: Morandell, Jasmin
  id: 4739D480-F248-11E8-B48F-1D18A9856A87
  last_name: Morandell
- first_name: Gaia
  full_name: Novarino, Gaia
  id: 3E57A680-F248-11E8-B48F-1D18A9856A87
  last_name: Novarino
  orcid: 0000-0002-7673-7178
citation:
  ama: Basilico B, Morandell J, Novarino G. Molecular mechanisms for targeted ASD
    treatments. <i>Current Opinion in Genetics and Development</i>. 2020;65(12):126-137.
    doi:<a href="https://doi.org/10.1016/j.gde.2020.06.004">10.1016/j.gde.2020.06.004</a>
  apa: Basilico, B., Morandell, J., &#38; Novarino, G. (2020). Molecular mechanisms
    for targeted ASD treatments. <i>Current Opinion in Genetics and Development</i>.
    Elsevier. <a href="https://doi.org/10.1016/j.gde.2020.06.004">https://doi.org/10.1016/j.gde.2020.06.004</a>
  chicago: Basilico, Bernadette, Jasmin Morandell, and Gaia Novarino. “Molecular Mechanisms
    for Targeted ASD Treatments.” <i>Current Opinion in Genetics and Development</i>.
    Elsevier, 2020. <a href="https://doi.org/10.1016/j.gde.2020.06.004">https://doi.org/10.1016/j.gde.2020.06.004</a>.
  ieee: B. Basilico, J. Morandell, and G. Novarino, “Molecular mechanisms for targeted
    ASD treatments,” <i>Current Opinion in Genetics and Development</i>, vol. 65,
    no. 12. Elsevier, pp. 126–137, 2020.
  ista: Basilico B, Morandell J, Novarino G. 2020. Molecular mechanisms for targeted
    ASD treatments. Current Opinion in Genetics and Development. 65(12), 126–137.
  mla: Basilico, Bernadette, et al. “Molecular Mechanisms for Targeted ASD Treatments.”
    <i>Current Opinion in Genetics and Development</i>, vol. 65, no. 12, Elsevier,
    2020, pp. 126–37, doi:<a href="https://doi.org/10.1016/j.gde.2020.06.004">10.1016/j.gde.2020.06.004</a>.
  short: B. Basilico, J. Morandell, G. Novarino, Current Opinion in Genetics and Development
    65 (2020) 126–137.
date_created: 2020-07-19T22:00:58Z
date_published: 2020-12-01T00:00:00Z
date_updated: 2024-09-10T12:04:25Z
day: '01'
ddc:
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department:
- _id: GaNo
doi: 10.1016/j.gde.2020.06.004
ec_funded: 1
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  call_identifier: H2020
  grant_number: '754411'
  name: ISTplus - Postdoctoral Fellowships
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  call_identifier: FWF
  grant_number: W1232-B24
  name: Molecular Drug Targets
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publication: Current Opinion in Genetics and Development
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scopus_import: '1'
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title: Molecular mechanisms for targeted ASD treatments
tmp:
  image: /images/cc_by_nc_nd.png
  legal_code_url: https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode
  name: Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
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type: journal_article
user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8
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year: '2020'
...
---
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abstract:
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  text: "The development of the human brain occurs through a tightly regulated series
    of dynamic and adaptive processes during prenatal and postnatal life. A disruption
    of this strictly orchestrated series of events can lead to a number of neurodevelopmental
    conditions, including Autism Spectrum Disorders (ASDs). ASDs are a very common,
    etiologically and phenotypically heterogeneous group of disorders sharing the
    core symptoms of social interaction and communication deficits and restrictive
    and repetitive interests and behaviors. They are estimated to affect one in 59
    individuals in the U.S. and, over the last three decades, mutations in more than
    a hundred genetic loci have been convincingly linked to ASD pathogenesis. Yet,
    for the vast majority of these ASD-risk genes their role during brain development
    and precise molecular function still remain elusive.\r\nDe novo loss of function
    mutations in the ubiquitin ligase-encoding gene Cullin 3 (CUL3) lead to ASD. In
    the study described here, we used Cul3 mouse models to evaluate the consequences
    of Cul3 mutations in vivo. Our results show that Cul3 heterozygous knockout mice
    exhibit deficits in motor coordination as well as ASD-relevant social and cognitive
    impairments. Cul3+/-, Cul3+/fl Emx1-Cre and Cul3fl/fl Emx1-Cre mutant brains display
    cortical lamination abnormalities due to defective migration of post-mitotic excitatory
    neurons, as well as reduced numbers of excitatory and inhibitory neurons. In line
    with the observed abnormal cortical organization, Cul3 heterozygous deletion is
    associated with decreased spontaneous excitatory and inhibitory activity in the
    cortex. At the molecular level we show that Cul3 regulates cytoskeletal and adhesion
    protein abundance in the mouse embryonic cortex. Abnormal regulation of cytoskeletal
    proteins in Cul3 mutant neural cells results in atypical organization of the actin
    mesh at the cell leading edge. Of note, heterozygous deletion of Cul3 in adult
    mice does not induce the majority of the behavioral defects observed in constitutive
    Cul3 haploinsufficient animals, pointing to a critical time-window for Cul3 deficiency.\r\nIn
    conclusion, our data indicate that Cul3 plays a critical role in the regulation
    of cytoskeletal proteins and neuronal migration. ASD-associated defects and behavioral
    abnormalities are primarily due to dosage sensitive Cul3 functions at early brain
    developmental stages."
acknowledged_ssus:
- _id: Bio
- _id: PreCl
acknowledgement: I would like to especially thank Armel Nicolas from the Proteomics
  and Christoph Sommer from the Bioimaging Facilities for the data analysis, and to
  thank the team of the Preclinical Facility, especially Sabina Deixler, Angela Schlerka,
  Anita Lepold, Mihalea Mihai and Michael Schun for taking care of the mouse line
  maintenance and their great support.
alternative_title:
- ISTA Thesis
article_processing_charge: No
author:
- first_name: Jasmin
  full_name: Morandell, Jasmin
  id: 4739D480-F248-11E8-B48F-1D18A9856A87
  last_name: Morandell
citation:
  ama: Morandell J. Illuminating the role of Cul3 in autism spectrum disorder pathogenesis.
    2020. doi:<a href="https://doi.org/10.15479/AT:ISTA:8620">10.15479/AT:ISTA:8620</a>
  apa: Morandell, J. (2020). <i>Illuminating the role of Cul3 in autism spectrum disorder
    pathogenesis</i>. Institute of Science and Technology Austria. <a href="https://doi.org/10.15479/AT:ISTA:8620">https://doi.org/10.15479/AT:ISTA:8620</a>
  chicago: Morandell, Jasmin. “Illuminating the Role of Cul3 in Autism Spectrum Disorder
    Pathogenesis.” Institute of Science and Technology Austria, 2020. <a href="https://doi.org/10.15479/AT:ISTA:8620">https://doi.org/10.15479/AT:ISTA:8620</a>.
  ieee: J. Morandell, “Illuminating the role of Cul3 in autism spectrum disorder pathogenesis,”
    Institute of Science and Technology Austria, 2020.
  ista: Morandell J. 2020. Illuminating the role of Cul3 in autism spectrum disorder
    pathogenesis. Institute of Science and Technology Austria.
  mla: Morandell, Jasmin. <i>Illuminating the Role of Cul3 in Autism Spectrum Disorder
    Pathogenesis</i>. Institute of Science and Technology Austria, 2020, doi:<a href="https://doi.org/10.15479/AT:ISTA:8620">10.15479/AT:ISTA:8620</a>.
  short: J. Morandell, Illuminating the Role of Cul3 in Autism Spectrum Disorder Pathogenesis,
    Institute of Science and Technology Austria, 2020.
date_created: 2020-10-07T14:53:13Z
date_published: 2020-10-12T00:00:00Z
date_updated: 2024-09-10T12:04:25Z
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title: Illuminating the role of Cul3 in autism spectrum disorder pathogenesis
type: dissertation
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...