---
_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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keyword:
- General Biochemistry
- Genetics and Molecular Biology
language:
- iso: eng
license: https://creativecommons.org/licenses/by/4.0/
month: '05'
oa: 1
oa_version: Published Version
project:
- _id: 260C2330-B435-11E9-9278-68D0E5697425
  call_identifier: H2020
  grant_number: '754411'
  name: ISTplus - Postdoctoral Fellowships
- _id: 25444568-B435-11E9-9278-68D0E5697425
  call_identifier: H2020
  grant_number: '715508'
  name: Probing the Reversibility of Autism Spectrum Disorders by Employing in vivo
    and in vitro Models
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  call_identifier: FWF
  grant_number: W1232-B24
  name: Molecular Drug Targets
- _id: 05A0D778-7A3F-11EA-A408-12923DDC885E
  grant_number: F07807
  name: Neural stem cells in autism and epilepsy
- _id: 265CB4D0-B435-11E9-9278-68D0E5697425
  call_identifier: FWF
  grant_number: I03600
  name: Optical control of synaptic function via adhesion molecules
publication: Nature Communications
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  eissn:
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publication_status: published
publisher: Springer Nature
quality_controlled: '1'
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  link:
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    url: https://ist.ac.at/en/news/defective-gene-slows-down-brain-cells/
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status: public
title: Cul3 regulates cytoskeleton protein homeostasis and cell migration during a
  critical window of brain development
tmp:
  image: /images/cc_by.png
  legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
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type: journal_article
user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8
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...
---
_id: '7800'
abstract:
- lang: eng
  text: 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.
acknowledged_ssus:
- _id: PreCl
article_processing_charge: No
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: 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: 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: 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>bioRxiv</i>. doi:<a href="https://doi.org/10.1101/2020.01.10.902064 ">10.1101/2020.01.10.902064
    </a>
  apa: Morandell, J., Schwarz, L. A., Basilico, B., Tasciyan, S., Nicolas, A., Sommer,
    C. M., … Novarino, G. (n.d.). Cul3 regulates cytoskeleton protein homeostasis
    and cell migration during a critical window of brain development. <i>bioRxiv</i>.
    Cold Spring Harbor Laboratory. <a href="https://doi.org/10.1101/2020.01.10.902064
    ">https://doi.org/10.1101/2020.01.10.902064 </a>
  chicago: Morandell, Jasmin, Lena A Schwarz, Bernadette Basilico, Saren Tasciyan,
    Armel Nicolas, Christoph M Sommer, Caroline Kreuzinger, et al. “Cul3 Regulates
    Cytoskeleton Protein Homeostasis and Cell Migration during a Critical Window of
    Brain Development.” <i>BioRxiv</i>. Cold Spring Harbor Laboratory, n.d. <a href="https://doi.org/10.1101/2020.01.10.902064
    ">https://doi.org/10.1101/2020.01.10.902064 </a>.
  ieee: J. Morandell <i>et al.</i>, “Cul3 regulates cytoskeleton protein homeostasis
    and cell migration during a critical window of brain development,” <i>bioRxiv</i>.
    Cold Spring Harbor Laboratory.
  ista: Morandell J, Schwarz LA, Basilico B, Tasciyan S, Nicolas A, Sommer CM, Kreuzinger
    C, Knaus L, Dobler Z, Cacci E, Danzl JG, Novarino G. Cul3 regulates cytoskeleton
    protein homeostasis and cell migration during a critical window of brain development.
    bioRxiv, <a href="https://doi.org/10.1101/2020.01.10.902064 ">10.1101/2020.01.10.902064
    </a>.
  mla: Morandell, Jasmin, et al. “Cul3 Regulates Cytoskeleton Protein Homeostasis
    and Cell Migration during a Critical Window of Brain Development.” <i>BioRxiv</i>,
    Cold Spring Harbor Laboratory, doi:<a href="https://doi.org/10.1101/2020.01.10.902064
    ">10.1101/2020.01.10.902064 </a>.
  short: J. Morandell, L.A. Schwarz, B. Basilico, S. Tasciyan, A. Nicolas, C.M. Sommer,
    C. Kreuzinger, L. Knaus, Z. Dobler, E. Cacci, J.G. Danzl, G. Novarino, BioRxiv
    (n.d.).
date_created: 2020-05-05T14:31:33Z
date_published: 2020-01-11T00:00:00Z
date_updated: 2024-09-10T12:04:26Z
day: '11'
ddc:
- '570'
department:
- _id: JoDa
- _id: GaNo
- _id: LifeSc
doi: '10.1101/2020.01.10.902064 '
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language:
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month: '01'
oa: 1
oa_version: Preprint
project:
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  call_identifier: FWF
  grant_number: I03600
  name: Optical control of synaptic function via adhesion molecules
- _id: 2548AE96-B435-11E9-9278-68D0E5697425
  call_identifier: FWF
  grant_number: W1232-B24
  name: Molecular Drug Targets
publication: bioRxiv
publication_status: submitted
publisher: Cold Spring Harbor Laboratory
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  - id: '8620'
    relation: dissertation_contains
    status: public
  - id: '9429'
    relation: later_version
    status: public
status: public
title: Cul3 regulates cytoskeleton protein homeostasis and cell migration during a
  critical window of brain development
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: preprint
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...
---
_id: '7415'
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: Armel
  full_name: Nicolas, Armel
  id: 2A103192-F248-11E8-B48F-1D18A9856A87
  last_name: Nicolas
- first_name: Lena A
  full_name: Schwarz, Lena A
  id: 29A8453C-F248-11E8-B48F-1D18A9856A87
  last_name: Schwarz
- 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, Nicolas A, Schwarz LA, Novarino G. S.16.05 Illuminating the role
    of the e3 ubiquitin ligase cullin3 in brain development and autism. <i>European
    Neuropsychopharmacology</i>. 2019;29(Supplement 6):S11-S12. doi:<a href="https://doi.org/10.1016/j.euroneuro.2019.09.040">10.1016/j.euroneuro.2019.09.040</a>
  apa: Morandell, J., Nicolas, A., Schwarz, L. A., &#38; Novarino, G. (2019). S.16.05
    Illuminating the role of the e3 ubiquitin ligase cullin3 in brain development
    and autism. <i>European Neuropsychopharmacology</i>. Elsevier. <a href="https://doi.org/10.1016/j.euroneuro.2019.09.040">https://doi.org/10.1016/j.euroneuro.2019.09.040</a>
  chicago: Morandell, Jasmin, Armel Nicolas, Lena A Schwarz, and Gaia Novarino. “S.16.05
    Illuminating the Role of the E3 Ubiquitin Ligase Cullin3 in Brain Development
    and Autism.” <i>European Neuropsychopharmacology</i>. Elsevier, 2019. <a href="https://doi.org/10.1016/j.euroneuro.2019.09.040">https://doi.org/10.1016/j.euroneuro.2019.09.040</a>.
  ieee: J. Morandell, A. Nicolas, L. A. Schwarz, and G. Novarino, “S.16.05 Illuminating
    the role of the e3 ubiquitin ligase cullin3 in brain development and autism,”
    <i>European Neuropsychopharmacology</i>, vol. 29, no. Supplement 6. Elsevier,
    pp. S11–S12, 2019.
  ista: Morandell J, Nicolas A, Schwarz LA, Novarino G. 2019. S.16.05 Illuminating
    the role of the e3 ubiquitin ligase cullin3 in brain development and autism. European
    Neuropsychopharmacology. 29(Supplement 6), S11–S12.
  mla: Morandell, Jasmin, et al. “S.16.05 Illuminating the Role of the E3 Ubiquitin
    Ligase Cullin3 in Brain Development and Autism.” <i>European Neuropsychopharmacology</i>,
    vol. 29, no. Supplement 6, Elsevier, 2019, pp. S11–12, doi:<a href="https://doi.org/10.1016/j.euroneuro.2019.09.040">10.1016/j.euroneuro.2019.09.040</a>.
  short: J. Morandell, A. Nicolas, L.A. Schwarz, G. Novarino, European Neuropsychopharmacology
    29 (2019) S11–S12.
date_created: 2020-01-30T10:07:41Z
date_published: 2019-12-13T00:00:00Z
date_updated: 2023-09-07T14:56:17Z
day: '13'
department:
- _id: GaNo
- _id: LifeSc
doi: 10.1016/j.euroneuro.2019.09.040
external_id:
  isi:
  - '000502657500021'
intvolume: '        29'
isi: 1
issue: Supplement 6
language:
- iso: eng
month: '12'
oa_version: None
page: S11-S12
publication: European Neuropsychopharmacology
publication_identifier:
  issn:
  - 0924-977X
publication_status: published
publisher: Elsevier
quality_controlled: '1'
status: public
title: S.16.05 Illuminating the role of the e3 ubiquitin ligase cullin3 in brain development
  and autism
type: journal_article
user_id: c635000d-4b10-11ee-a964-aac5a93f6ac1
volume: 29
year: '2019'
...