---
_id: '12401'
abstract:
- lang: eng
text: "Detachment of the cancer cells from the bulk of the tumor is the first step
of metastasis, which\r\nis the primary cause of cancer related deaths. It is unclear,
which factors contribute to this step.\r\nRecent studies indicate a crucial role
of the tumor microenvironment in malignant\r\ntransformation and metastasis. Studying
cancer cell invasion and detachments quantitatively in\r\nthe context of its physiological
microenvironment is technically challenging. Especially, precise\r\ncontrol of
microenvironmental properties in vivo is currently not possible. Here, I studied
the\r\nrole of microenvironment geometry in the invasion and detachment of cancer
cells from the\r\nbulk with a simplistic and reductionist approach. In this approach,
I engineered microfluidic\r\ndevices to mimic a pseudo 3D extracellular matrix
environment, where I was able to\r\nquantitatively tune the geometrical configuration
of the microenvironment and follow tumor\r\ncells with fluorescence live imaging.
To aid quantitative analysis I developed a widely applicable\r\nsoftware application
to automatically analyze and visualize particle tracking data.\r\nQuantitative
analysis of tumor cell invasion in isotropic and anisotropic microenvironments\r\nshowed
that heterogeneity in the microenvironment promotes faster invasion and more\r\nfrequent
detachment of cells. These observations correlated with overall higher speed of
cells at\r\nthe edge of the bulk of the cells. In heterogeneous microenvironments
cells preferentially\r\npassed through larger pores, thus invading areas of least
resistance and generating finger-like\r\ninvasive structures. The detachments
occurred mostly at the tips of these structures.\r\nTo investigate the potential
mechanism, we established a two dimensional model to simulate\r\nactive Brownian
particles representing the cell nuclei dynamics. These simulations backed our
in\r\nvitro observations without the need of precise fitting the simulation parameters.
Our model\r\nsuggests the importance of the pore heterogeneity in the direction
perpendicular to the\r\norientation of bias field (lateral heterogeneity), which
causes the interface roughening."
alternative_title:
- ISTA Thesis
article_processing_charge: No
author:
- first_name: Saren
full_name: Tasciyan, Saren
id: 4323B49C-F248-11E8-B48F-1D18A9856A87
last_name: Tasciyan
orcid: 0000-0003-1671-393X
citation:
ama: Tasciyan S. Role of microenvironment heterogeneity in cancer cell invasion.
2022. doi:10.15479/at:ista:12401
apa: Tasciyan, S. (2022). Role of microenvironment heterogeneity in cancer cell
invasion. Institute of Science and Technology Austria. https://doi.org/10.15479/at:ista:12401
chicago: Tasciyan, Saren. “Role of Microenvironment Heterogeneity in Cancer Cell
Invasion.” Institute of Science and Technology Austria, 2022. https://doi.org/10.15479/at:ista:12401.
ieee: S. Tasciyan, “Role of microenvironment heterogeneity in cancer cell invasion,”
Institute of Science and Technology Austria, 2022.
ista: Tasciyan S. 2022. Role of microenvironment heterogeneity in cancer cell invasion.
Institute of Science and Technology Austria.
mla: Tasciyan, Saren. Role of Microenvironment Heterogeneity in Cancer Cell Invasion.
Institute of Science and Technology Austria, 2022, doi:10.15479/at:ista:12401.
short: S. Tasciyan, Role of Microenvironment Heterogeneity in Cancer Cell Invasion,
Institute of Science and Technology Austria, 2022.
date_created: 2023-01-26T11:55:16Z
date_published: 2022-12-22T00:00:00Z
date_updated: 2024-09-10T12:04:26Z
day: '22'
ddc:
- '610'
degree_awarded: PhD
department:
- _id: GradSch
- _id: MiSi
doi: 10.15479/at:ista:12401
file:
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checksum: cc4a2b4a7e3c4ee8ef7f2dbf909b12bd
content_type: application/pdf
creator: cchlebak
date_created: 2023-01-26T11:58:14Z
date_updated: 2023-12-21T23:30:03Z
embargo: 2023-12-20
file_id: '12402'
file_name: PhD-Thesis_Saren Tasciyan_formatted_aftercrash_fixed_600dpi_95pc_final_PDFA3b.pdf
file_size: 42059787
relation: main_file
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checksum: f1b4ca98b8ab0cb043b1830971e9bd9c
content_type: application/x-zip-compressed
creator: cchlebak
date_created: 2023-01-26T12:00:10Z
date_updated: 2023-12-21T23:30:03Z
embargo_to: open_access
file_id: '12403'
file_name: Source Files - Saren Tasciyan - PhD Thesis.zip
file_size: 261256696
relation: source_file
file_date_updated: 2023-12-21T23:30:03Z
has_accepted_license: '1'
language:
- iso: eng
month: '12'
oa: 1
oa_version: Published Version
page: '105'
publication_identifier:
issn:
- 2663-337X
publication_status: published
publisher: Institute of Science and Technology Austria
related_material:
record:
- id: '679'
relation: part_of_dissertation
status: public
- id: '10703'
relation: part_of_dissertation
status: public
- id: '7885'
relation: part_of_dissertation
status: public
- id: '9429'
relation: part_of_dissertation
status: public
status: public
supervisor:
- first_name: Michael K
full_name: Sixt, Michael K
id: 41E9FBEA-F248-11E8-B48F-1D18A9856A87
last_name: Sixt
orcid: 0000-0002-6620-9179
title: Role of microenvironment heterogeneity in cancer cell invasion
type: dissertation
user_id: 8b945eb4-e2f2-11eb-945a-df72226e66a9
year: '2022'
...
---
_id: '10703'
abstract:
- lang: eng
text: 'When crawling through the body, leukocytes often traverse tissues that are
densely packed with extracellular matrix and other cells, and this raises the
question: How do leukocytes overcome compressive mechanical loads? Here, we show
that the actin cortex of leukocytes is mechanoresponsive and that this responsiveness
requires neither force sensing via the nucleus nor adhesive interactions with
a substrate. Upon global compression of the cell body as well as local indentation
of the plasma membrane, Wiskott-Aldrich syndrome protein (WASp) assembles into
dot-like structures, providing activation platforms for Arp2/3 nucleated actin
patches. These patches locally push against the external load, which can be obstructing
collagen fibers or other cells, and thereby create space to facilitate forward
locomotion. We show in vitro and in vivo that this WASp function is rate limiting
for ameboid leukocyte migration in dense but not in loose environments and is
required for trafficking through diverse tissues such as skin and lymph nodes.'
acknowledged_ssus:
- _id: LifeSc
- _id: Bio
- _id: EM-Fac
acknowledgement: We thank N. Darwish-Miranda, F. Leite, F.P. Assen, and A. Eichner
for advice and help with experiments. We thank J. Renkawitz, E. Kiermaier, A. Juanes
Garcia, and M. Avellaneda for critical reading of the manuscript. We thank M. Driscoll
for advice on fluorescent labeling of collagen gels. This research was supported
by the Scientific Service Units (SSUs) of IST Austria through resources provided
by Molecular Biology Services/Lab Support Facility (LSF)/Bioimaging Facility/Electron
Microscopy Facility. This work was funded by grants from the European Research Council
( CoG 724373 ) and the Austrian Science Foundation (FWF) to M.S. F.G. received funding
from the European Union’s Horizon 2020 research and innovation program under the
Marie Skłodowska-Curie grant agreement no. 747687.
article_processing_charge: No
article_type: original
author:
- first_name: Florian
full_name: Gaertner, Florian
last_name: Gaertner
- first_name: Patricia
full_name: Reis-Rodrigues, Patricia
last_name: Reis-Rodrigues
- first_name: Ingrid
full_name: De Vries, Ingrid
id: 4C7D837E-F248-11E8-B48F-1D18A9856A87
last_name: De Vries
- first_name: Miroslav
full_name: Hons, Miroslav
id: 4167FE56-F248-11E8-B48F-1D18A9856A87
last_name: Hons
orcid: 0000-0002-6625-3348
- first_name: Juan
full_name: Aguilera, Juan
last_name: Aguilera
- first_name: Michael
full_name: Riedl, Michael
id: 3BE60946-F248-11E8-B48F-1D18A9856A87
last_name: Riedl
orcid: 0000-0003-4844-6311
- first_name: Alexander F
full_name: Leithner, Alexander F
id: 3B1B77E4-F248-11E8-B48F-1D18A9856A87
last_name: Leithner
orcid: 0000-0002-1073-744X
- first_name: Saren
full_name: Tasciyan, Saren
id: 4323B49C-F248-11E8-B48F-1D18A9856A87
last_name: Tasciyan
orcid: 0000-0003-1671-393X
- first_name: Aglaja
full_name: Kopf, Aglaja
id: 31DAC7B6-F248-11E8-B48F-1D18A9856A87
last_name: Kopf
orcid: 0000-0002-2187-6656
- first_name: Jack
full_name: Merrin, Jack
id: 4515C308-F248-11E8-B48F-1D18A9856A87
last_name: Merrin
orcid: 0000-0001-5145-4609
- first_name: Vanessa
full_name: Zheden, Vanessa
id: 39C5A68A-F248-11E8-B48F-1D18A9856A87
last_name: Zheden
orcid: 0000-0002-9438-4783
- first_name: Walter
full_name: Kaufmann, Walter
id: 3F99E422-F248-11E8-B48F-1D18A9856A87
last_name: Kaufmann
orcid: 0000-0001-9735-5315
- first_name: Robert
full_name: Hauschild, Robert
id: 4E01D6B4-F248-11E8-B48F-1D18A9856A87
last_name: Hauschild
orcid: 0000-0001-9843-3522
- first_name: Michael K
full_name: Sixt, Michael K
id: 41E9FBEA-F248-11E8-B48F-1D18A9856A87
last_name: Sixt
orcid: 0000-0002-6620-9179
citation:
ama: Gaertner F, Reis-Rodrigues P, de Vries I, et al. WASp triggers mechanosensitive
actin patches to facilitate immune cell migration in dense tissues. Developmental
Cell. 2022;57(1):47-62.e9. doi:10.1016/j.devcel.2021.11.024
apa: Gaertner, F., Reis-Rodrigues, P., de Vries, I., Hons, M., Aguilera, J., Riedl,
M., … Sixt, M. K. (2022). WASp triggers mechanosensitive actin patches to facilitate
immune cell migration in dense tissues. Developmental Cell. Cell Press ;
Elsevier. https://doi.org/10.1016/j.devcel.2021.11.024
chicago: Gaertner, Florian, Patricia Reis-Rodrigues, Ingrid de Vries, Miroslav Hons,
Juan Aguilera, Michael Riedl, Alexander F Leithner, et al. “WASp Triggers Mechanosensitive
Actin Patches to Facilitate Immune Cell Migration in Dense Tissues.” Developmental
Cell. Cell Press ; Elsevier, 2022. https://doi.org/10.1016/j.devcel.2021.11.024.
ieee: F. Gaertner et al., “WASp triggers mechanosensitive actin patches to
facilitate immune cell migration in dense tissues,” Developmental Cell,
vol. 57, no. 1. Cell Press ; Elsevier, p. 47–62.e9, 2022.
ista: Gaertner F, Reis-Rodrigues P, de Vries I, Hons M, Aguilera J, Riedl M, Leithner
AF, Tasciyan S, Kopf A, Merrin J, Zheden V, Kaufmann W, Hauschild R, Sixt MK.
2022. WASp triggers mechanosensitive actin patches to facilitate immune cell migration
in dense tissues. Developmental Cell. 57(1), 47–62.e9.
mla: Gaertner, Florian, et al. “WASp Triggers Mechanosensitive Actin Patches to
Facilitate Immune Cell Migration in Dense Tissues.” Developmental Cell,
vol. 57, no. 1, Cell Press ; Elsevier, 2022, p. 47–62.e9, doi:10.1016/j.devcel.2021.11.024.
short: F. Gaertner, P. Reis-Rodrigues, I. de Vries, M. Hons, J. Aguilera, M. Riedl,
A.F. Leithner, S. Tasciyan, A. Kopf, J. Merrin, V. Zheden, W. Kaufmann, R. Hauschild,
M.K. Sixt, Developmental Cell 57 (2022) 47–62.e9.
date_created: 2022-01-30T23:01:33Z
date_published: 2022-01-10T00:00:00Z
date_updated: 2024-03-25T23:30:12Z
day: '10'
ddc:
- '570'
department:
- _id: MiSi
- _id: EM-Fac
- _id: NanoFab
- _id: BjHo
doi: 10.1016/j.devcel.2021.11.024
ec_funded: 1
external_id:
isi:
- '000768933800005'
pmid:
- '34919802'
intvolume: ' 57'
isi: 1
issue: '1'
language:
- iso: eng
main_file_link:
- open_access: '1'
url: https://www.sciencedirect.com/science/article/pii/S1534580721009497
month: '01'
oa: 1
oa_version: Published Version
page: 47-62.e9
pmid: 1
project:
- _id: 260AA4E2-B435-11E9-9278-68D0E5697425
call_identifier: H2020
grant_number: '747687'
name: Mechanical Adaptation of Lamellipodial Actin Networks in Migrating Cells
- _id: 25FE9508-B435-11E9-9278-68D0E5697425
call_identifier: H2020
grant_number: '724373'
name: Cellular navigation along spatial gradients
publication: Developmental Cell
publication_identifier:
eissn:
- 1878-1551
issn:
- 1534-5807
publication_status: published
publisher: Cell Press ; Elsevier
quality_controlled: '1'
related_material:
record:
- id: '12726'
relation: dissertation_contains
status: public
- id: '14530'
relation: dissertation_contains
status: public
- id: '12401'
relation: dissertation_contains
status: public
scopus_import: '1'
status: public
title: WASp triggers mechanosensitive actin patches to facilitate immune cell migration
in dense tissues
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
(CC BY-NC-ND 4.0)
short: CC BY-NC-ND (4.0)
type: journal_article
user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8
volume: 57
year: '2022'
...
---
_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.
Nature Communications. 2021;12(1). doi:10.1038/s41467-021-23123-x
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. Nature Communications.
Springer Nature. https://doi.org/10.1038/s41467-021-23123-x
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.”
Nature Communications. Springer Nature, 2021. https://doi.org/10.1038/s41467-021-23123-x.
ieee: J. Morandell et al., “Cul3 regulates cytoskeleton protein homeostasis
and cell migration during a critical window of brain development,” Nature Communications,
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.” Nature Communications,
vol. 12, no. 1, 3058, Springer Nature, 2021, doi:10.1038/s41467-021-23123-x.
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:
isi:
- '000658769900010'
file:
- access_level: open_access
checksum: 337e0f7959c35ec959984cacdcb472ba
content_type: application/pdf
creator: kschuh
date_created: 2021-05-28T12:39:43Z
date_updated: 2021-05-28T12:39:43Z
file_id: '9430'
file_name: 2021_NatureCommunications_Morandell.pdf
file_size: 9358599
relation: main_file
success: 1
file_date_updated: 2021-05-28T12:39:43Z
has_accepted_license: '1'
intvolume: ' 12'
isi: 1
issue: '1'
keyword:
- General Biochemistry
- Genetics and Molecular Biology
language:
- iso: eng
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
- _id: 2548AE96-B435-11E9-9278-68D0E5697425
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
publication_identifier:
eissn:
- 2041-1723
publication_status: published
publisher: Springer Nature
quality_controlled: '1'
related_material:
link:
- relation: press_release
url: https://ist.ac.at/en/news/defective-gene-slows-down-brain-cells/
record:
- id: '7800'
relation: earlier_version
status: public
- id: '12401'
relation: dissertation_contains
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.png
legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
short: CC BY (4.0)
type: journal_article
user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8
volume: 12
year: '2021'
...
---
_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.
bioRxiv. doi:10.1101/2020.01.10.902064
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. bioRxiv.
Cold Spring Harbor Laboratory. https://doi.org/10.1101/2020.01.10.902064
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.” BioRxiv. Cold Spring Harbor Laboratory, n.d. https://doi.org/10.1101/2020.01.10.902064 .
ieee: J. Morandell et al., “Cul3 regulates cytoskeleton protein homeostasis
and cell migration during a critical window of brain development,” bioRxiv.
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, 10.1101/2020.01.10.902064
.
mla: Morandell, Jasmin, et al. “Cul3 Regulates Cytoskeleton Protein Homeostasis
and Cell Migration during a Critical Window of Brain Development.” BioRxiv,
Cold Spring Harbor Laboratory, doi:10.1101/2020.01.10.902064 .
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 '
file:
- access_level: open_access
checksum: c6799ab5daba80efe8e2ed63c15f8c81
content_type: application/pdf
creator: rsix
date_created: 2020-05-05T14:31:19Z
date_updated: 2020-07-14T12:48:03Z
file_id: '7801'
file_name: 2020.01.10.902064v1.full.pdf
file_size: 2931370
relation: main_file
file_date_updated: 2020-07-14T12:48:03Z
has_accepted_license: '1'
language:
- iso: eng
month: '01'
oa: 1
oa_version: Preprint
project:
- _id: 265CB4D0-B435-11E9-9278-68D0E5697425
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
related_material:
record:
- 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
(CC BY-NC-ND 4.0)
short: CC BY-NC-ND (4.0)
type: preprint
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
year: '2020'
...
---
_id: '7885'
abstract:
- lang: eng
text: Eukaryotic cells migrate by coupling the intracellular force of the actin
cytoskeleton to the environment. While force coupling is usually mediated by transmembrane
adhesion receptors, especially those of the integrin family, amoeboid cells such
as leukocytes can migrate extremely fast despite very low adhesive forces1. Here
we show that leukocytes cannot only migrate under low adhesion but can also transmit
forces in the complete absence of transmembrane force coupling. When confined
within three-dimensional environments, they use the topographical features of
the substrate to propel themselves. Here the retrograde flow of the actin cytoskeleton
follows the texture of the substrate, creating retrograde shear forces that are
sufficient to drive the cell body forwards. Notably, adhesion-dependent and adhesion-independent
migration are not mutually exclusive, but rather are variants of the same principle
of coupling retrograde actin flow to the environment and thus can potentially
operate interchangeably and simultaneously. As adhesion-free migration is independent
of the chemical composition of the environment, it renders cells completely autonomous
in their locomotive behaviour.
acknowledged_ssus:
- _id: Bio
- _id: LifeSc
- _id: M-Shop
acknowledgement: We thank A. Leithner and J. Renkawitz for discussion and critical
reading of the manuscript; J. Schwarz and M. Mehling for establishing the microfluidic
setups; the Bioimaging Facility of IST Austria for excellent support, as well as
the Life Science Facility and the Miba Machine Shop of IST Austria; and F. N. Arslan,
L. E. Burnett and L. Li for their work during their rotation in the IST PhD programme.
This work was supported by the European Research Council (ERC StG 281556 and CoG
724373) to M.S. and grants from the Austrian Science Fund (FWF P29911) and the WWTF
to M.S. M.H. was supported by the European Regional Development Fund Project (CZ.02.1.01/0.0/0.0/15_003/0000476).
F.G. received funding from the European Union’s Horizon 2020 research and innovation
programme under the Marie Skłodowska-Curie grant agreement no. 747687.
article_processing_charge: No
article_type: original
author:
- first_name: Anne
full_name: Reversat, Anne
id: 35B76592-F248-11E8-B48F-1D18A9856A87
last_name: Reversat
orcid: 0000-0003-0666-8928
- first_name: Florian R
full_name: Gärtner, Florian R
id: 397A88EE-F248-11E8-B48F-1D18A9856A87
last_name: Gärtner
orcid: 0000-0001-6120-3723
- first_name: Jack
full_name: Merrin, Jack
id: 4515C308-F248-11E8-B48F-1D18A9856A87
last_name: Merrin
orcid: 0000-0001-5145-4609
- first_name: Julian A
full_name: Stopp, Julian A
id: 489E3F00-F248-11E8-B48F-1D18A9856A87
last_name: Stopp
- first_name: Saren
full_name: Tasciyan, Saren
id: 4323B49C-F248-11E8-B48F-1D18A9856A87
last_name: Tasciyan
orcid: 0000-0003-1671-393X
- first_name: Juan L
full_name: Aguilera Servin, Juan L
id: 2A67C376-F248-11E8-B48F-1D18A9856A87
last_name: Aguilera Servin
orcid: 0000-0002-2862-8372
- first_name: Ingrid
full_name: De Vries, Ingrid
id: 4C7D837E-F248-11E8-B48F-1D18A9856A87
last_name: De Vries
- first_name: Robert
full_name: Hauschild, Robert
id: 4E01D6B4-F248-11E8-B48F-1D18A9856A87
last_name: Hauschild
orcid: 0000-0001-9843-3522
- first_name: Miroslav
full_name: Hons, Miroslav
id: 4167FE56-F248-11E8-B48F-1D18A9856A87
last_name: Hons
orcid: 0000-0002-6625-3348
- first_name: Matthieu
full_name: Piel, Matthieu
last_name: Piel
- first_name: Andrew
full_name: Callan-Jones, Andrew
last_name: Callan-Jones
- first_name: Raphael
full_name: Voituriez, Raphael
last_name: Voituriez
- first_name: Michael K
full_name: Sixt, Michael K
id: 41E9FBEA-F248-11E8-B48F-1D18A9856A87
last_name: Sixt
orcid: 0000-0002-6620-9179
citation:
ama: Reversat A, Gärtner FR, Merrin J, et al. Cellular locomotion using environmental
topography. Nature. 2020;582:582–585. doi:10.1038/s41586-020-2283-z
apa: Reversat, A., Gärtner, F. R., Merrin, J., Stopp, J. A., Tasciyan, S., Aguilera
Servin, J. L., … Sixt, M. K. (2020). Cellular locomotion using environmental topography.
Nature. Springer Nature. https://doi.org/10.1038/s41586-020-2283-z
chicago: Reversat, Anne, Florian R Gärtner, Jack Merrin, Julian A Stopp, Saren Tasciyan,
Juan L Aguilera Servin, Ingrid de Vries, et al. “Cellular Locomotion Using Environmental
Topography.” Nature. Springer Nature, 2020. https://doi.org/10.1038/s41586-020-2283-z.
ieee: A. Reversat et al., “Cellular locomotion using environmental topography,”
Nature, vol. 582. Springer Nature, pp. 582–585, 2020.
ista: Reversat A, Gärtner FR, Merrin J, Stopp JA, Tasciyan S, Aguilera Servin JL,
de Vries I, Hauschild R, Hons M, Piel M, Callan-Jones A, Voituriez R, Sixt MK.
2020. Cellular locomotion using environmental topography. Nature. 582, 582–585.
mla: Reversat, Anne, et al. “Cellular Locomotion Using Environmental Topography.”
Nature, vol. 582, Springer Nature, 2020, pp. 582–585, doi:10.1038/s41586-020-2283-z.
short: A. Reversat, F.R. Gärtner, J. Merrin, J.A. Stopp, S. Tasciyan, J.L. Aguilera
Servin, I. de Vries, R. Hauschild, M. Hons, M. Piel, A. Callan-Jones, R. Voituriez,
M.K. Sixt, Nature 582 (2020) 582–585.
date_created: 2020-05-24T22:01:01Z
date_published: 2020-06-25T00:00:00Z
date_updated: 2024-03-25T23:30:12Z
day: '25'
department:
- _id: NanoFab
- _id: Bio
- _id: MiSi
doi: 10.1038/s41586-020-2283-z
ec_funded: 1
external_id:
isi:
- '000532688300008'
intvolume: ' 582'
isi: 1
language:
- iso: eng
month: '06'
oa_version: None
page: 582–585
project:
- _id: 25A603A2-B435-11E9-9278-68D0E5697425
call_identifier: FP7
grant_number: '281556'
name: Cytoskeletal force generation and force transduction of migrating leukocytes
- _id: 25FE9508-B435-11E9-9278-68D0E5697425
call_identifier: H2020
grant_number: '724373'
name: Cellular navigation along spatial gradients
- _id: 26018E70-B435-11E9-9278-68D0E5697425
call_identifier: FWF
grant_number: P29911
name: Mechanical adaptation of lamellipodial actin
- _id: 260AA4E2-B435-11E9-9278-68D0E5697425
call_identifier: H2020
grant_number: '747687'
name: Mechanical Adaptation of Lamellipodial Actin Networks in Migrating Cells
publication: Nature
publication_identifier:
eissn:
- '14764687'
issn:
- '00280836'
publication_status: published
publisher: Springer Nature
quality_controlled: '1'
related_material:
link:
- description: News on IST Homepage
relation: press_release
url: https://ist.ac.at/en/news/off-road-mode-enables-mobile-cells-to-move-freely/
record:
- id: '14697'
relation: dissertation_contains
status: public
- id: '12401'
relation: dissertation_contains
status: public
scopus_import: '1'
status: public
title: Cellular locomotion using environmental topography
type: journal_article
user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8
volume: 582
year: '2020'
...
---
_id: '679'
abstract:
- lang: eng
text: Protective responses against pathogens require a rapid mobilization of resting
neutrophils and the timely removal of activated ones. Neutrophils are exceptionally
short-lived leukocytes, yet it remains unclear whether the lifespan of pathogen-engaged
neutrophils is regulated differently from that in the circulating steady-state
pool. Here, we have found that under homeostatic conditions, the mRNA-destabilizing
protein tristetraprolin (TTP) regulates apoptosis and the numbers of activated
infiltrating murine neutrophils but not neutrophil cellularity. Activated TTP-deficient
neutrophils exhibited decreased apoptosis and enhanced accumulation at the infection
site. In the context of myeloid-specific deletion of Ttp, the potentiation of
neutrophil deployment protected mice against lethal soft tissue infection with
Streptococcus pyogenes and prevented bacterial dissemination. Neutrophil transcriptome
analysis revealed that decreased apoptosis of TTP-deficient neutrophils was specifically
associated with elevated expression of myeloid cell leukemia 1 (Mcl1) but not
other antiapoptotic B cell leukemia/ lymphoma 2 (Bcl2) family members. Higher
Mcl1 expression resulted from stabilization of Mcl1 mRNA in the absence of TTP.
The low apoptosis rate of infiltrating TTP-deficient neutrophils was comparable
to that of transgenic Mcl1-overexpressing neutrophils. Our study demonstrates
that posttranscriptional gene regulation by TTP schedules the termination of the
antimicrobial engagement of neutrophils. The balancing role of TTP comes at the
cost of an increased risk of bacterial infections.
acknowledgement: This work was supported by grants from the Austrian Science Fund
(FWF) (P27538-B21, I1621-B22, and SFB 43, to PK); by funding from the European Union
Seventh Framework Programme Marie Curie Initial Training Networks (FP7-PEOPLE-2012-ITN)
for the project INBIONET (INfection BIOlogy Training NETwork under grant agreement
PITN-GA-2012-316682; and by a joint research cluster initiative of the University
of Vienna and the Medical University of Vienna.
author:
- first_name: Florian
full_name: Ebner, Florian
last_name: Ebner
- first_name: Vitaly
full_name: Sedlyarov, Vitaly
last_name: Sedlyarov
- first_name: Saren
full_name: Tasciyan, Saren
id: 4323B49C-F248-11E8-B48F-1D18A9856A87
last_name: Tasciyan
orcid: 0000-0003-1671-393X
- first_name: Masa
full_name: Ivin, Masa
last_name: Ivin
- first_name: Franz
full_name: Kratochvill, Franz
last_name: Kratochvill
- first_name: Nina
full_name: Gratz, Nina
last_name: Gratz
- first_name: Lukas
full_name: Kenner, Lukas
last_name: Kenner
- first_name: Andreas
full_name: Villunger, Andreas
last_name: Villunger
- first_name: Michael K
full_name: Sixt, Michael K
id: 41E9FBEA-F248-11E8-B48F-1D18A9856A87
last_name: Sixt
orcid: 0000-0002-6620-9179
- first_name: Pavel
full_name: Kovarik, Pavel
last_name: Kovarik
citation:
ama: Ebner F, Sedlyarov V, Tasciyan S, et al. The RNA-binding protein tristetraprolin
schedules apoptosis of pathogen-engaged neutrophils during bacterial infection.
The Journal of Clinical Investigation. 2017;127(6):2051-2065. doi:10.1172/JCI80631
apa: Ebner, F., Sedlyarov, V., Tasciyan, S., Ivin, M., Kratochvill, F., Gratz, N.,
… Kovarik, P. (2017). The RNA-binding protein tristetraprolin schedules apoptosis
of pathogen-engaged neutrophils during bacterial infection. The Journal of
Clinical Investigation. American Society for Clinical Investigation. https://doi.org/10.1172/JCI80631
chicago: Ebner, Florian, Vitaly Sedlyarov, Saren Tasciyan, Masa Ivin, Franz Kratochvill,
Nina Gratz, Lukas Kenner, Andreas Villunger, Michael K Sixt, and Pavel Kovarik.
“The RNA-Binding Protein Tristetraprolin Schedules Apoptosis of Pathogen-Engaged
Neutrophils during Bacterial Infection.” The Journal of Clinical Investigation.
American Society for Clinical Investigation, 2017. https://doi.org/10.1172/JCI80631.
ieee: F. Ebner et al., “The RNA-binding protein tristetraprolin schedules
apoptosis of pathogen-engaged neutrophils during bacterial infection,” The
Journal of Clinical Investigation, vol. 127, no. 6. American Society for Clinical
Investigation, pp. 2051–2065, 2017.
ista: Ebner F, Sedlyarov V, Tasciyan S, Ivin M, Kratochvill F, Gratz N, Kenner L,
Villunger A, Sixt MK, Kovarik P. 2017. The RNA-binding protein tristetraprolin
schedules apoptosis of pathogen-engaged neutrophils during bacterial infection.
The Journal of Clinical Investigation. 127(6), 2051–2065.
mla: Ebner, Florian, et al. “The RNA-Binding Protein Tristetraprolin Schedules Apoptosis
of Pathogen-Engaged Neutrophils during Bacterial Infection.” The Journal of
Clinical Investigation, vol. 127, no. 6, American Society for Clinical Investigation,
2017, pp. 2051–65, doi:10.1172/JCI80631.
short: F. Ebner, V. Sedlyarov, S. Tasciyan, M. Ivin, F. Kratochvill, N. Gratz, L.
Kenner, A. Villunger, M.K. Sixt, P. Kovarik, The Journal of Clinical Investigation
127 (2017) 2051–2065.
date_created: 2018-12-11T11:47:53Z
date_published: 2017-06-01T00:00:00Z
date_updated: 2024-03-25T23:30:12Z
day: '01'
department:
- _id: MiSi
doi: 10.1172/JCI80631
external_id:
pmid:
- '28504646'
intvolume: ' 127'
issue: '6'
language:
- iso: eng
main_file_link:
- open_access: '1'
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5451238/
month: '06'
oa: 1
oa_version: Submitted Version
page: 2051 - 2065
pmid: 1
project:
- _id: 25985A36-B435-11E9-9278-68D0E5697425
call_identifier: FWF
grant_number: T00817-B21
name: The biochemical basis of PAR polarization
- _id: 25E9AF9E-B435-11E9-9278-68D0E5697425
call_identifier: FWF
grant_number: P27201-B22
name: Revealing the mechanisms underlying drug interactions
publication: The Journal of Clinical Investigation
publication_identifier:
issn:
- '00219738'
publication_status: published
publisher: American Society for Clinical Investigation
publist_id: '7038'
quality_controlled: '1'
related_material:
record:
- id: '12401'
relation: dissertation_contains
status: public
scopus_import: 1
status: public
title: The RNA-binding protein tristetraprolin schedules apoptosis of pathogen-engaged
neutrophils during bacterial infection
type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 127
year: '2017'
...