---
_id: '13107'
abstract:
- lang: eng
text: "Within the human body, the brain exhibits the highest rate of energy consumption
amongst all organs, with the majority of generated ATP being utilized to sustain
neuronal activity. Therefore, the metabolism of the mature cerebral cortex is
geared towards preserving metabolic homeostasis whilst generating significant
amounts of energy. This requires a precise interplay between diverse metabolic
pathways, spanning from a tissue-wide scale to the level of individual neurons.
Disturbances to this delicate metabolic equilibrium, such as those resulting from
maternal malnutrition\r\nor mutations affecting metabolic enzymes, often result
in neuropathological variants of neurodevelopment. For instance, mutations in
SLC7A5, a transporter of metabolically essential large neutral amino acids (LNAAs),
have been associated with autism and microcephaly. However, despite recent progress
in the field, the extent of metabolic restructuring that occurs within the developing
brain and the corresponding alterations in nutrient demands during various critical
periods remain largely unknown. To investigate this, we performed metabolomic
profiling of the murine cerebral cortex to characterize the metabolic state of
the forebrain at different developmental stages. We found that the developing
cortex undergoes substantial metabolic reprogramming, with specific sets of metabolites
displaying stage-specific changes. According to our observations, we determined
a distinct temporal period in postnatal development during which the cortex displays
heightened reliance on LNAAs. Hence, using a conditional knock-out mouse model,
we deleted Slc7a5 in neural cells, allowing us to monitor the impact of a perturbed
neuronal metabolic state across multiple developmental stages of corticogenesis.
We found that manipulating the levels of essential LNAAs in cortical neurons in
vivo affects one particular perinatal developmental period critical for cortical
network refinement. Abnormally low intracellular LNAA levels result in cell-autonomous
alterations in neuronal lipid metabolism, excitability, and survival during this
particular time window. Although most of the effects of Slc7a5 deletion on neuronal
physiology are transient, derailment of these processes during this brief but
crucial window leads to long-term circuit dysfunction in mice. In conclusion,
out data indicate that the cerebral cortex undergoes significant metabolic reorganization
during development. This process involves the intricate integration of multiple
metabolic pathways to ensure optimal neuronal function throughout different developmental
stages. Our findings offer a paradigm for understanding how neurons synchronize
the expression of nutrient-related genes with their activity to allow proper brain
maturation. Further, our results demonstrate that disruptions in these precisely
calibrated metabolic processes during critical periods of brain development may
result in neuropathological outcomes in mice and in humans."
acknowledged_ssus:
- _id: PreCl
- _id: Bio
- _id: EM-Fac
alternative_title:
- ISTA Thesis
article_processing_charge: No
author:
- first_name: Lisa
full_name: Knaus, Lisa
id: 3B2ABCF4-F248-11E8-B48F-1D18A9856A87
last_name: Knaus
citation:
ama: 'Knaus L. The metabolism of the developing brain : How large neutral amino
acids modulate perinatal neuronal excitability and survival. 2023. doi:10.15479/at:ista:13107'
apa: 'Knaus, L. (2023). The metabolism of the developing brain : How large neutral
amino acids modulate perinatal neuronal excitability and survival. Institute
of Science and Technology Austria. https://doi.org/10.15479/at:ista:13107'
chicago: 'Knaus, Lisa. “The Metabolism of the Developing Brain : How Large Neutral
Amino Acids Modulate Perinatal Neuronal Excitability and Survival.” Institute
of Science and Technology Austria, 2023. https://doi.org/10.15479/at:ista:13107.'
ieee: 'L. Knaus, “The metabolism of the developing brain : How large neutral amino
acids modulate perinatal neuronal excitability and survival,” Institute of Science
and Technology Austria, 2023.'
ista: 'Knaus L. 2023. The metabolism of the developing brain : How large neutral
amino acids modulate perinatal neuronal excitability and survival. Institute of
Science and Technology Austria.'
mla: 'Knaus, Lisa. The Metabolism of the Developing Brain : How Large Neutral
Amino Acids Modulate Perinatal Neuronal Excitability and Survival. Institute
of Science and Technology Austria, 2023, doi:10.15479/at:ista:13107.'
short: 'L. Knaus, The Metabolism of the Developing Brain : How Large Neutral Amino
Acids Modulate Perinatal Neuronal Excitability and Survival, Institute of Science
and Technology Austria, 2023.'
date_created: 2023-06-01T09:05:24Z
date_published: 2023-05-31T00:00:00Z
date_updated: 2024-02-07T08:03:33Z
day: '31'
ddc:
- '570'
degree_awarded: PhD
department:
- _id: GradSch
- _id: GaNo
doi: 10.15479/at:ista:13107
ec_funded: 1
file:
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checksum: 4b69a4ac0bbf4163d59c0b58dcb4f2c3
content_type: application/vnd.openxmlformats-officedocument.wordprocessingml.document
creator: lknaus
date_created: 2023-06-01T13:48:41Z
date_updated: 2023-06-01T13:48:41Z
file_id: '13112'
file_name: Thesis_Lisa Knaus_approved_final.docx
file_size: 12991551
relation: source_file
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creator: lknaus
date_created: 2023-06-02T09:47:29Z
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file_id: '13114'
file_name: Thesis_Lisa Knaus_approved_final_pdfa2b.pdf
file_size: 9309015
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file_date_updated: 2023-06-07T08:41:49Z
has_accepted_license: '1'
language:
- iso: eng
month: '05'
oa: 1
oa_version: Published Version
page: '147'
project:
- _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
publication_identifier:
issn:
- 2663 - 337X
publication_status: published
publisher: Institute of Science and Technology Austria
related_material:
record:
- id: '12802'
relation: part_of_dissertation
status: public
status: public
supervisor:
- first_name: Gaia
full_name: Novarino, Gaia
id: 3E57A680-F248-11E8-B48F-1D18A9856A87
last_name: Novarino
orcid: 0000-0002-7673-7178
title: 'The metabolism of the developing brain : How large neutral amino acids modulate
perinatal neuronal excitability and survival'
type: dissertation
user_id: 8b945eb4-e2f2-11eb-945a-df72226e66a9
year: '2023'
...
---
_id: '12802'
abstract:
- lang: eng
text: Little is known about the critical metabolic changes that neural cells have
to undergo during development and how temporary shifts in this program can influence
brain circuitries and behavior. Inspired by the discovery that mutations in SLC7A5,
a transporter of metabolically essential large neutral amino acids (LNAAs), lead
to autism, we employed metabolomic profiling to study the metabolic states of
the cerebral cortex across different developmental stages. We found that the forebrain
undergoes significant metabolic remodeling throughout development, with certain
groups of metabolites showing stage-specific changes, but what are the consequences
of perturbing this metabolic program? By manipulating Slc7a5 expression in neural
cells, we found that the metabolism of LNAAs and lipids are interconnected in
the cortex. Deletion of Slc7a5 in neurons affects the postnatal metabolic state,
leading to a shift in lipid metabolism. Additionally, it causes stage- and cell-type-specific
alterations in neuronal activity patterns, resulting in a long-term circuit dysfunction.
acknowledged_ssus:
- _id: PreCl
- _id: EM-Fac
- _id: Bio
- _id: LifeSc
acknowledgement: We thank A. Freeman and V. Voronin for technical assistance, S. Deixler,
A. Stichelberger, M. Schunn, and the Preclinical Facility for managing our animal
colony. We thank L. Andersen and J. Sonntag, who were involved in generating the
MADM lines. We thank the ISTA LSF Mass Spectrometry Core Facility for assistance
with the proteomic analysis, as well as the ISTA electron microscopy and Imaging
and Optics facility for technical support. Metabolomics LC-MS/MS analysis was performed
by the Metabolomics Facility at Vienna BioCenter Core Facilities (VBCF). We acknowledge
the support of the EMBL Metabolomics Core Facility (MCF) for lipidomics and intracellular
metabolomics mass spectrometry data acquisition and analysis. RNA sequencing was
performed by the Next Generation Sequencing Facility at VBCF. Schematics were generated
using Biorender.com. This work was supported by the Austrian Science Fund (FWF,
DK W1232-B24) and by the European Union’s Horizon 2020 research and innovation program
(ERC) grant 725780 (LinPro) to S.H. and 715508 (REVERSEAUTISM) to G.N.
article_processing_charge: Yes (via OA deal)
article_type: original
author:
- first_name: Lisa
full_name: Knaus, Lisa
id: 3B2ABCF4-F248-11E8-B48F-1D18A9856A87
last_name: Knaus
- first_name: Bernadette
full_name: Basilico, Bernadette
id: 36035796-5ACA-11E9-A75E-7AF2E5697425
last_name: Basilico
orcid: 0000-0003-1843-3173
- first_name: Daniel
full_name: Malzl, Daniel
last_name: Malzl
- first_name: Maria
full_name: Gerykova Bujalkova, Maria
last_name: Gerykova Bujalkova
- first_name: Mateja
full_name: Smogavec, Mateja
last_name: Smogavec
- first_name: Lena A.
full_name: Schwarz, Lena A.
last_name: Schwarz
- first_name: Sarah
full_name: Gorkiewicz, Sarah
id: f141a35d-15a9-11ec-9fb2-fef6becc7b6f
last_name: Gorkiewicz
- first_name: Nicole
full_name: Amberg, Nicole
id: 4CD6AAC6-F248-11E8-B48F-1D18A9856A87
last_name: Amberg
orcid: 0000-0002-3183-8207
- first_name: Florian
full_name: Pauler, Florian
id: 48EA0138-F248-11E8-B48F-1D18A9856A87
last_name: Pauler
orcid: 0000-0002-7462-0048
- first_name: Christian
full_name: Knittl-Frank, Christian
last_name: Knittl-Frank
- first_name: Marianna
full_name: Tassinari, Marianna
id: 7af593f1-d44a-11ed-bf94-a3646a6bb35e
last_name: Tassinari
- first_name: Nuno
full_name: Maulide, Nuno
last_name: Maulide
- first_name: Thomas
full_name: Rülicke, Thomas
last_name: Rülicke
- first_name: Jörg
full_name: Menche, Jörg
last_name: Menche
- first_name: Simon
full_name: Hippenmeyer, Simon
id: 37B36620-F248-11E8-B48F-1D18A9856A87
last_name: Hippenmeyer
orcid: 0000-0003-2279-1061
- first_name: Gaia
full_name: Novarino, Gaia
id: 3E57A680-F248-11E8-B48F-1D18A9856A87
last_name: Novarino
orcid: 0000-0002-7673-7178
citation:
ama: Knaus L, Basilico B, Malzl D, et al. Large neutral amino acid levels tune perinatal
neuronal excitability and survival. Cell. 2023;186(9):1950-1967.e25. doi:10.1016/j.cell.2023.02.037
apa: Knaus, L., Basilico, B., Malzl, D., Gerykova Bujalkova, M., Smogavec, M., Schwarz,
L. A., … Novarino, G. (2023). Large neutral amino acid levels tune perinatal neuronal
excitability and survival. Cell. Elsevier. https://doi.org/10.1016/j.cell.2023.02.037
chicago: Knaus, Lisa, Bernadette Basilico, Daniel Malzl, Maria Gerykova Bujalkova,
Mateja Smogavec, Lena A. Schwarz, Sarah Gorkiewicz, et al. “Large Neutral Amino
Acid Levels Tune Perinatal Neuronal Excitability and Survival.” Cell. Elsevier,
2023. https://doi.org/10.1016/j.cell.2023.02.037.
ieee: L. Knaus et al., “Large neutral amino acid levels tune perinatal neuronal
excitability and survival,” Cell, vol. 186, no. 9. Elsevier, p. 1950–1967.e25,
2023.
ista: Knaus L, Basilico B, Malzl D, Gerykova Bujalkova M, Smogavec M, Schwarz LA,
Gorkiewicz S, Amberg N, Pauler F, Knittl-Frank C, Tassinari M, Maulide N, Rülicke
T, Menche J, Hippenmeyer S, Novarino G. 2023. Large neutral amino acid levels
tune perinatal neuronal excitability and survival. Cell. 186(9), 1950–1967.e25.
mla: Knaus, Lisa, et al. “Large Neutral Amino Acid Levels Tune Perinatal Neuronal
Excitability and Survival.” Cell, vol. 186, no. 9, Elsevier, 2023, p. 1950–1967.e25,
doi:10.1016/j.cell.2023.02.037.
short: L. Knaus, B. Basilico, D. Malzl, M. Gerykova Bujalkova, M. Smogavec, L.A.
Schwarz, S. Gorkiewicz, N. Amberg, F. Pauler, C. Knittl-Frank, M. Tassinari, N.
Maulide, T. Rülicke, J. Menche, S. Hippenmeyer, G. Novarino, Cell 186 (2023) 1950–1967.e25.
date_created: 2023-04-05T08:15:40Z
date_published: 2023-04-27T00:00:00Z
date_updated: 2024-02-07T08:03:32Z
day: '27'
ddc:
- '570'
department:
- _id: SiHi
- _id: GaNo
doi: 10.1016/j.cell.2023.02.037
ec_funded: 1
external_id:
isi:
- '000991468700001'
file:
- access_level: open_access
checksum: 47e94fbe19e86505b429cb7a5b503ce6
content_type: application/pdf
creator: dernst
date_created: 2023-05-02T09:26:21Z
date_updated: 2023-05-02T09:26:21Z
file_id: '12889'
file_name: 2023_Cell_Knaus.pdf
file_size: 15712841
relation: main_file
success: 1
file_date_updated: 2023-05-02T09:26:21Z
has_accepted_license: '1'
intvolume: ' 186'
isi: 1
issue: '9'
keyword:
- General Biochemistry
- Genetics and Molecular Biology
language:
- iso: eng
month: '04'
oa: 1
oa_version: Published Version
page: 1950-1967.e25
project:
- _id: 2548AE96-B435-11E9-9278-68D0E5697425
call_identifier: FWF
grant_number: W1232-B24
name: Molecular Drug Targets
- _id: 260018B0-B435-11E9-9278-68D0E5697425
call_identifier: H2020
grant_number: '725780'
name: Principles of Neural Stem Cell Lineage Progression in Cerebral Cortex Development
- _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
publication: Cell
publication_identifier:
issn:
- 0092-8674
publication_status: published
publisher: Elsevier
quality_controlled: '1'
related_material:
link:
- description: News on ISTA Website
relation: press_release
url: https://ista.ac.at/en/news/feed-them-or-lose-them/
record:
- id: '13107'
relation: dissertation_contains
status: public
scopus_import: '1'
status: public
title: Large neutral amino acid levels tune perinatal neuronal excitability and survival
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: 186
year: '2023'
...
---
_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: '10281'
abstract:
- lang: eng
text: Mutations affecting mTOR or RAS signaling underlie defined syndromes (the
so-called mTORopathies and RASopathies) with high risk for Autism Spectrum Disorder
(ASD). These syndromes show a broad variety of somatic phenotypes including cancers,
skin abnormalities, heart disease and facial dysmorphisms. Less well studied are
the neuropsychiatric symptoms such as ASD. Here, we assess the relevance of these
signalopathies in ASD reviewing genetic, human cell model, rodent studies and
clinical trials. We conclude that signalopathies have an increased liability for
ASD and that, in particular, ASD individuals with dysmorphic features and intellectual
disability (ID) have a higher chance for disruptive mutations in RAS- and mTOR-related
genes. Studies on rodent and human cell models confirm aberrant neuronal development
as the underlying pathology. Human studies further suggest that multiple hits
are necessary to induce the respective phenotypes. Recent clinical trials do only
report improvements for comorbid conditions such as epilepsy or cancer but not
for behavioral aspects. Animal models show that treatment during early development
can rescue behavioral phenotypes. Taken together, we suggest investigating the
differential roles of mTOR and RAS signaling in both human and rodent models,
and to test drug treatment both during and after neuronal development in the available
model systems
acknowledgement: 'This review was funded by the IMI2 Initiative under the grant AIMS-2-TRIALS
No 777394, by the Hessian Ministry for Science and Arts; State of Hesse Ministry
for Science and Arts: LOEWE-Grant to the CePTER-Consortium (www.uni-frankfurt.de/67689811);
Research (BMBF) under the grant RAISE-genic No 779282 all to AGC. This work was
also supported by the European Union’s Horizon 2020 research and innovation program
(ERC) grant 715508 (REVERSEAUTISM) and by the Austrian Science Fund (FWF) (DK W1232-B24)
both to G.N. and both BMBF GeNeRARe 01GM1519A and CRC 1080, project B10, of the
German Research Foundation (DFG) to M.J.S, respectively. We want to thank R. Waltes
for her support in preparing this manuscript.'
alternative_title:
- Special Issue "From Genes to Therapy in Autism Spectrum Disorder"
article_number: '1746'
article_processing_charge: No
article_type: original
author:
- first_name: Verica
full_name: Vasic, Verica
last_name: Vasic
- first_name: Mattson S.O.
full_name: Jones, Mattson S.O.
last_name: Jones
- first_name: Denise
full_name: Haslinger, Denise
id: 76922BDA-3D3B-11EA-90BD-A44F3DDC885E
last_name: Haslinger
- first_name: Lisa
full_name: Knaus, Lisa
id: 3B2ABCF4-F248-11E8-B48F-1D18A9856A87
last_name: Knaus
- first_name: Michael J.
full_name: Schmeisser, Michael J.
last_name: Schmeisser
- first_name: Gaia
full_name: Novarino, Gaia
id: 3E57A680-F248-11E8-B48F-1D18A9856A87
last_name: Novarino
orcid: 0000-0002-7673-7178
- first_name: Andreas G.
full_name: Chiocchetti, Andreas G.
last_name: Chiocchetti
citation:
ama: 'Vasic V, Jones MSO, Haslinger D, et al. Translating the role of mtor-and ras-associated
signalopathies in autism spectrum disorder: Models, mechanisms and treatment.
Genes. 2021;12(11). doi:10.3390/genes12111746'
apa: 'Vasic, V., Jones, M. S. O., Haslinger, D., Knaus, L., Schmeisser, M. J., Novarino,
G., & Chiocchetti, A. G. (2021). Translating the role of mtor-and ras-associated
signalopathies in autism spectrum disorder: Models, mechanisms and treatment.
Genes. MDPI. https://doi.org/10.3390/genes12111746'
chicago: 'Vasic, Verica, Mattson S.O. Jones, Denise Haslinger, Lisa Knaus, Michael
J. Schmeisser, Gaia Novarino, and Andreas G. Chiocchetti. “Translating the Role
of Mtor-and Ras-Associated Signalopathies in Autism Spectrum Disorder: Models,
Mechanisms and Treatment.” Genes. MDPI, 2021. https://doi.org/10.3390/genes12111746.'
ieee: 'V. Vasic et al., “Translating the role of mtor-and ras-associated
signalopathies in autism spectrum disorder: Models, mechanisms and treatment,”
Genes, vol. 12, no. 11. MDPI, 2021.'
ista: 'Vasic V, Jones MSO, Haslinger D, Knaus L, Schmeisser MJ, Novarino G, Chiocchetti
AG. 2021. Translating the role of mtor-and ras-associated signalopathies in autism
spectrum disorder: Models, mechanisms and treatment. Genes. 12(11), 1746.'
mla: 'Vasic, Verica, et al. “Translating the Role of Mtor-and Ras-Associated Signalopathies
in Autism Spectrum Disorder: Models, Mechanisms and Treatment.” Genes,
vol. 12, no. 11, 1746, MDPI, 2021, doi:10.3390/genes12111746.'
short: V. Vasic, M.S.O. Jones, D. Haslinger, L. Knaus, M.J. Schmeisser, G. Novarino,
A.G. Chiocchetti, Genes 12 (2021).
date_created: 2021-11-14T23:01:24Z
date_published: 2021-10-30T00:00:00Z
date_updated: 2023-08-14T11:46:12Z
day: '30'
ddc:
- '570'
department:
- _id: GaNo
doi: 10.3390/genes12111746
ec_funded: 1
external_id:
isi:
- '000834044200002'
file:
- access_level: open_access
checksum: 256cb832a9c3051c7dc741f6423b8cbd
content_type: application/pdf
creator: dernst
date_created: 2022-05-16T07:02:27Z
date_updated: 2022-05-16T07:02:27Z
file_id: '11380'
file_name: 2021_Genes_Vasic.pdf
file_size: 1335308
relation: main_file
success: 1
file_date_updated: 2022-05-16T07:02:27Z
has_accepted_license: '1'
intvolume: ' 12'
isi: 1
issue: '11'
language:
- iso: eng
month: '10'
oa: 1
oa_version: Published Version
project:
- _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
publication: Genes
publication_identifier:
eissn:
- 2073-4425
publication_status: published
publisher: MDPI
quality_controlled: '1'
scopus_import: '1'
status: public
title: 'Translating the role of mtor-and ras-associated signalopathies in autism spectrum
disorder: Models, mechanisms and treatment'
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
license: https://creativecommons.org/licenses/by-nc-nd/4.0/
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: '7414'
article_processing_charge: No
article_type: original
author:
- first_name: Lisa
full_name: Knaus, Lisa
id: 3B2ABCF4-F248-11E8-B48F-1D18A9856A87
last_name: Knaus
- first_name: Dora-Clara
full_name: Tarlungeanu, Dora-Clara
id: 2ABCE612-F248-11E8-B48F-1D18A9856A87
last_name: Tarlungeanu
- first_name: Gaia
full_name: Novarino, Gaia
id: 3E57A680-F248-11E8-B48F-1D18A9856A87
last_name: Novarino
orcid: 0000-0002-7673-7178
citation:
ama: Knaus L, Tarlungeanu D-C, Novarino G. S.16.03 A homozygous missense mutation
in SLC7A5 leads to autism spectrum disorder and microcephaly. European Neuropsychopharmacology.
2019;29(Supplement 6):S11. doi:10.1016/j.euroneuro.2019.09.039
apa: Knaus, L., Tarlungeanu, D.-C., & Novarino, G. (2019). S.16.03 A homozygous
missense mutation in SLC7A5 leads to autism spectrum disorder and microcephaly.
European Neuropsychopharmacology. Elsevier. https://doi.org/10.1016/j.euroneuro.2019.09.039
chicago: Knaus, Lisa, Dora-Clara Tarlungeanu, and Gaia Novarino. “S.16.03 A Homozygous
Missense Mutation in SLC7A5 Leads to Autism Spectrum Disorder and Microcephaly.”
European Neuropsychopharmacology. Elsevier, 2019. https://doi.org/10.1016/j.euroneuro.2019.09.039.
ieee: L. Knaus, D.-C. Tarlungeanu, and G. Novarino, “S.16.03 A homozygous missense
mutation in SLC7A5 leads to autism spectrum disorder and microcephaly,” European
Neuropsychopharmacology, vol. 29, no. Supplement 6. Elsevier, p. S11, 2019.
ista: Knaus L, Tarlungeanu D-C, Novarino G. 2019. S.16.03 A homozygous missense
mutation in SLC7A5 leads to autism spectrum disorder and microcephaly. European
Neuropsychopharmacology. 29(Supplement 6), S11.
mla: Knaus, Lisa, et al. “S.16.03 A Homozygous Missense Mutation in SLC7A5 Leads
to Autism Spectrum Disorder and Microcephaly.” European Neuropsychopharmacology,
vol. 29, no. Supplement 6, Elsevier, 2019, p. S11, doi:10.1016/j.euroneuro.2019.09.039.
short: L. Knaus, D.-C. Tarlungeanu, G. Novarino, European Neuropsychopharmacology
29 (2019) S11.
date_created: 2020-01-30T10:06:15Z
date_published: 2019-12-13T00:00:00Z
date_updated: 2023-09-07T14:55:23Z
day: '13'
department:
- _id: GaNo
doi: 10.1016/j.euroneuro.2019.09.039
external_id:
isi:
- '000502657500020'
intvolume: ' 29'
isi: 1
issue: Supplement 6
language:
- iso: eng
month: '12'
oa_version: None
page: S11
publication: European Neuropsychopharmacology
publication_identifier:
issn:
- 0924-977X
publication_status: published
publisher: Elsevier
quality_controlled: '1'
status: public
title: S.16.03 A homozygous missense mutation in SLC7A5 leads to autism spectrum disorder
and microcephaly
type: journal_article
user_id: c635000d-4b10-11ee-a964-aac5a93f6ac1
volume: 29
year: '2019'
...