---
OA_place: publisher
OA_type: hybrid
PlanS_conform: '1'
_id: '22295'
abstract:
- lang: eng
  text: 'Despite the functional diversity of over 100 causal genes1,2,3, phenotypic
    convergence across models may reveal common neurobiological processes in autism
    spectrum disorder (ASD). Here we profiled 251 samples from 11 monogenic mouse
    models of ASD using single-nucleus multi-omic sequencing across three developmental
    stages, both sexes and two brain regions. Despite genetic heterogeneity, ASD-linked
    mutations converged on perturbations of the radial glial cell lineage. These alterations
    reflect a transient developmental delay rather than lasting lineage misspecification
    and resolve by postnatal stages. Molecularly, the largest transcriptional differences
    emerged in neurons at early postnatal stages. These changes included downregulation
    of synaptic and ion channel-related genes, consistent with homeostatic adaptation
    or delayed maturation. Network analysis showed molecular convergence across models
    within each developmental stage, suggesting that diverse mutations linked to ASD
    impinge on common, stage-specific processes. Convergence becomes less pronounced
    by postnatal day 14, highlighting the dynamic nature of ASD-associated changes.
    Cross-genotype heterogeneity is superimposed on stage-specific effects. Electrophysiology
    corroborated this pattern: mutants generally showed altered neuronal excitability
    and synaptic properties with model-specific nuances. Our study also highlighted
    sex-specific gene expression alterations, with female mice often displaying larger
    effect sizes than male mice. Together, our findings provide a comprehensive view
    of developmental cellular and molecular dynamics across models of ASD.'
acknowledged_ssus:
- _id: Bio
- _id: LifeSc
acknowledgement: We thank F. Freeman, V. Voronin and M. Ladron de Guevara for technical
  assistance; A. Stichelberger and S. Liegenfeld for the management of our animal
  colony; M. Schunn, C. Gold and the Preclinical Facility team for technical assistance;
  C. Jansen and the Scientific Computing Facility for bioinformatics support and technical
  assistance; the Biomedical Sequencing Facility at CeMM for assistance with next-generation
  sequencing; and J. Lin and T. Krausgruber in the laboratory of C. Bock for support
  with flow cytometry; J. Kirchner for illustrating the multi-omics approach depicted
  in Fig. 1; and all members of the laboratory of G.N. for their support and discussions.
  This study was supported by the Scientific Service Units of ISTA through resources
  provided by the Imaging & Optics Facility and the Laboratory Support Facility. Bulk
  RNA-seq was performed by the Next Generation Sequencing Facility at Vienna BioCenter
  Core Facilities, member of the Vienna BioCenter. This work was supported by a European
  Research Council Consolidator Grant (PR1028ERC02), by SFARI (PR1028SIM02) and by
  the Austrian Science Fund (PE1028W1232 and PR1028FG1803) to G.N. Open access funding
  provided by Institute of Science and Technology (IST Austria).
article_processing_charge: Yes (via OA deal)
article_type: original
author:
- first_name: Lena A
  full_name: Schwarz, Lena A
  id: 29A8453C-F248-11E8-B48F-1D18A9856A87
  last_name: Schwarz
- first_name: Christoph
  full_name: Dotter, Christoph
  id: 4C66542E-F248-11E8-B48F-1D18A9856A87
  last_name: Dotter
  orcid: 0000-0002-9033-9096
- first_name: Sergey
  full_name: Isaev, Sergey
  last_name: Isaev
- first_name: Michela
  full_name: Lisi, Michela
  id: 39383c1b-d3eb-11ef-8d6c-c8cdf4e10c8c
  last_name: Lisi
- first_name: Daniel
  full_name: Malzl, Daniel
  last_name: Malzl
- first_name: Christoph
  full_name: Büschl, Christoph
  id: 2a8c054c-0913-11ee-9159-f8ef515809ed
  last_name: Büschl
- first_name: Sabrina
  full_name: Ladstätter, Sabrina
  last_name: Ladstätter
- first_name: Bárbara
  full_name: Oliveira, Bárbara
  id: 3B03AA1A-F248-11E8-B48F-1D18A9856A87
  last_name: Oliveira
- first_name: Matteo
  full_name: Barel, Matteo
  id: 8959927b-2236-11ed-bd6e-ea83d94ade0e
  last_name: Barel
- first_name: Bernadette
  full_name: Basilico, Bernadette
  id: 36035796-5ACA-11E9-A75E-7AF2E5697425
  last_name: Basilico
  orcid: 0000-0003-1843-3173
- first_name: Chaitanya
  full_name: Chintaluri, Chaitanya
  id: BA06AFEE-A4BA-11EA-AE5C-14673DDC885E
  last_name: Chintaluri
  orcid: 0000-0003-4252-1608
- first_name: Sarah
  full_name: Gorkiewicz, Sarah
  id: f141a35d-15a9-11ec-9fb2-fef6becc7b6f
  last_name: Gorkiewicz
- first_name: Mohammad
  full_name: Goudarzi, Mohammad
  id: 3384113A-F248-11E8-B48F-1D18A9856A87
  last_name: Goudarzi
- first_name: Tereza
  full_name: Belinova, Tereza
  id: 0bf89b6a-d28b-11eb-8bd6-f43768e4d368
  last_name: Belinova
- first_name: Stephan
  full_name: Reichl, Stephan
  last_name: Reichl
- first_name: Gintarė
  full_name: Sendžikaitė, Gintarė
  id: dd6d52f2-c50d-11eb-9548-bcf0ff82b344
  last_name: Sendžikaitė
- first_name: Satish
  full_name: Arcot Jayaram, Satish
  id: b0bbee33-09f7-11eb-909c-8b358058d28a
  last_name: Arcot Jayaram
  orcid: 0000-0002-2479-2669
- first_name: Peter
  full_name: Koppensteiner, Peter
  id: 3B8B25A8-F248-11E8-B48F-1D18A9856A87
  last_name: Koppensteiner
  orcid: 0000-0002-3509-1948
- 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: Tim P
  full_name: Vogels, Tim P
  id: CB6FF8D2-008F-11EA-8E08-2637E6697425
  last_name: Vogels
  orcid: 0000-0003-3295-6181
- first_name: Jörg
  full_name: Menche, Jörg
  last_name: Menche
- first_name: Igor
  full_name: Adameyko, Igor
  last_name: Adameyko
- first_name: Peter Vasili
  full_name: Kharchenko, Peter Vasili
  id: 0095641e-7eb7-11f1-8665-aec51a2ab5e0
  last_name: Kharchenko
- first_name: Christoph
  full_name: Bock, Christoph
  last_name: Bock
- first_name: Gaia
  full_name: Novarino, Gaia
  id: 3E57A680-F248-11E8-B48F-1D18A9856A87
  last_name: Novarino
  orcid: 0000-0002-7673-7178
citation:
  ama: Schwarz LA, Dotter C, Isaev S, et al. Cortical development dynamics across
    autism spectrum disorder mouse models. <i>Nature</i>. 2026. doi:<a href="https://doi.org/10.1038/s41586-026-10679-1">10.1038/s41586-026-10679-1</a>
  apa: Schwarz, L. A., Dotter, C., Isaev, S., Lisi, M., Malzl, D., Büschl, C., … Novarino,
    G. (2026). Cortical development dynamics across autism spectrum disorder mouse
    models. <i>Nature</i>. Springer Nature. <a href="https://doi.org/10.1038/s41586-026-10679-1">https://doi.org/10.1038/s41586-026-10679-1</a>
  chicago: Schwarz, Lena A, Christoph Dotter, Sergey Isaev, Michela Lisi, Daniel Malzl,
    Christoph Büschl, Sabrina Ladstätter, et al. “Cortical Development Dynamics across
    Autism Spectrum Disorder Mouse Models.” <i>Nature</i>. Springer Nature, 2026.
    <a href="https://doi.org/10.1038/s41586-026-10679-1">https://doi.org/10.1038/s41586-026-10679-1</a>.
  ieee: L. A. Schwarz <i>et al.</i>, “Cortical development dynamics across autism
    spectrum disorder mouse models,” <i>Nature</i>. Springer Nature, 2026.
  ista: Schwarz LA, Dotter C, Isaev S, Lisi M, Malzl D, Büschl C, Ladstätter S, Oliveira
    B, Barel M, Basilico B, Chintaluri C, Gorkiewicz S, Goudarzi M, Belinova T, Reichl
    S, Sendžikaitė G, Arcot Jayaram S, Koppensteiner P, Sommer CM, Vogels TP, Menche
    J, Adameyko I, Kharchenko PV, Bock C, Novarino G. 2026. Cortical development dynamics
    across autism spectrum disorder mouse models. Nature.
  mla: Schwarz, Lena A., et al. “Cortical Development Dynamics across Autism Spectrum
    Disorder Mouse Models.” <i>Nature</i>, Springer Nature, 2026, doi:<a href="https://doi.org/10.1038/s41586-026-10679-1">10.1038/s41586-026-10679-1</a>.
  short: L.A. Schwarz, C. Dotter, S. Isaev, M. Lisi, D. Malzl, C. Büschl, S. Ladstätter,
    B. Oliveira, M. Barel, B. Basilico, C. Chintaluri, S. Gorkiewicz, M. Goudarzi,
    T. Belinova, S. Reichl, G. Sendžikaitė, S. Arcot Jayaram, P. Koppensteiner, C.M.
    Sommer, T.P. Vogels, J. Menche, I. Adameyko, P.V. Kharchenko, C. Bock, G. Novarino,
    Nature (2026).
corr_author: '1'
dataavailabilitystatement: Single-nucleus multiomics data are available from the Gene
  Expression Omnibus (GSE328363). The mm10 reference genome was used for the alignment
  (refdata-cellranger-arc-mm10-2020-A-2.0.0, obtained from https://cf.10xgenomics.com/supp/cell-arc/refdata-cellranger-arc-mm10-2020-A-2.0.0.tar.gz).
  Single-cell data can be accessed and visualized through a CELLxGENE database (https://adameykolab.hifo.meduniwien.ac.at/cellxgene_public/filecrawl/.2026_Nature_Schwarz).
  Source data are provided with this paper. Scripts and analyses that support the
  main findings of this study are accessible in a GitHub repository (https://git.ista.ac.at/research-sofware/mouseome).
date_created: 2026-07-13T09:47:21Z
date_published: 2026-06-17T00:00:00Z
date_updated: 2026-08-04T09:29:55Z
day: '17'
ddc:
- '570'
department:
- _id: AnKi
- _id: GaNo
- _id: TiVo
- _id: ScienComp
- _id: GradSch
- _id: Bio
- _id: PreCl
doi: 10.1038/s41586-026-10679-1
external_id:
  pmid:
  - '42310454'
fulldoi: https://doi.org/10.1038/s41586-026-10679-1
has_accepted_license: '1'
language:
- iso: eng
main_file_link:
- open_access: '1'
  url: https://doi.org/10.1038/s41586-026-10679-1
month: '06'
oa: 1
oa_version: Published Version
pmid: 1
project:
- _id: 34ba8964-11ca-11ed-8bc3-e15864e7e9a6
  grant_number: '101044865'
  name: Toward an understanding of the brain interstitial system and the extracellular
    proteome in health and autism spectrum disorders
- _id: 9B91375C-BA93-11EA-9121-9846C619BF3A
  grant_number: '707964'
  name: Critical windows and reversibility of ASD associated with mutations in chromatin
    remodelers
- _id: 2548AE96-B435-11E9-9278-68D0E5697425
  call_identifier: FWF
  grant_number: W1232
  name: Molecular Drug Targets
- _id: ebb38b5d-77a9-11ec-83b8-a42e08120a88
  grant_number: FG1803 49015
  name: Neurobiology of anxiety in autism spectrum disorders
publication: Nature
publication_identifier:
  eissn:
  - 1476-4687
  issn:
  - 0028-0836
publication_status: epub_ahead
publisher: Springer Nature
quality_controlled: '1'
related_material:
  link:
  - description: News on ISTA website
    relation: press_release
    url: https://ista.ac.at/en/news/patterns-in-genetic-chaos/
researchdata_availability: yes
scopus_import: '1'
status: public
supplementarymaterial: yes
title: Cortical development dynamics across autism spectrum disorder mouse models
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: ba8df636-2132-11f1-aed0-ed93e2281fdd
year: '2026'
...
---
OA_place: publisher
OA_type: hybrid
PlanS_conform: '1'
_id: '19704'
abstract:
- lang: eng
  text: The information-processing capability of the brain’s cellular network depends
    on the physical wiring pattern between neurons and their molecular and functional
    characteristics. Mapping neurons and resolving their individual synaptic connections
    can be achieved by volumetric imaging at nanoscale resolution1,2 with dense cellular
    labelling. Light microscopy is uniquely positioned to visualize specific molecules,
    but dense, synapse-level circuit reconstruction by light microscopy has been out
    of reach, owing to limitations in resolution, contrast and volumetric imaging
    capability. Here we describe light-microscopy-based connectomics (LICONN). We
    integrated specifically engineered hydrogel embedding and expansion with comprehensive
    deep-learning-based segmentation and analysis of connectivity, thereby directly
    incorporating molecular information into synapse-level reconstructions of brain
    tissue. LICONN will allow synapse-level phenotyping of brain tissue in biological
    experiments in a readily adoptable manner.
acknowledged_ssus:
- _id: Bio
- _id: LifeSc
- _id: ScienComp
- _id: PreCl
- _id: M-Shop
- _id: E-Lib
acknowledgement: 'We thank S. Dorkenwald and P. Li for critical reading of the manuscript,
  S. Loomba for discussions and E. Miguel for support with data handling. We acknowledge
  support from ISTA’s scientific service units: Imaging and Optics, Lab Support, Scientific
  Computing, the preclinical facility, the Miba Machine Shop and the library. We acknowledge
  funding from the following sources: Austrian Science Fund (FWF) grant DK W1232 (J.G.D.
  and M.R.T.); Austrian Academy of Sciences DOC fellowship 26137 (M.R.T.); Gesellschaft
  für Forschungsförderung NÖ (NFB) grant LSC18-022 (J.G.D.); the European Union’s
  Horizon 2020 research and innovation programme and Marie Skłodowska-Curie Actions
  Fellowship 665385 (J.L.); and the European Union’s Horizon 2020 research and innovation
  programme and European Research Council (ERC) grant 101044865 ‘SecretAutism’ (G.N.).Open
  access funding provided by Institute of Science and Technology (IST Austria).'
article_processing_charge: Yes (via OA deal)
article_type: original
author:
- first_name: Mojtaba
  full_name: Tavakoli, Mojtaba
  id: 3A0A06F4-F248-11E8-B48F-1D18A9856A87
  last_name: Tavakoli
  orcid: 0000-0002-7667-6854
- first_name: Julia
  full_name: Lyudchik, Julia
  id: 46E28B80-F248-11E8-B48F-1D18A9856A87
  last_name: Lyudchik
- first_name: Michał
  full_name: Januszewski, Michał
  last_name: Januszewski
- first_name: Vitali
  full_name: Vistunou, Vitali
  id: 7e146587-8972-11ed-ae7b-d7a32ea86a81
  last_name: Vistunou
- first_name: Nathalie
  full_name: Agudelo Duenas, Nathalie
  id: 40E7F008-F248-11E8-B48F-1D18A9856A87
  last_name: Agudelo Duenas
- first_name: Jakob
  full_name: Vorlaufer, Jakob
  id: 937696FA-C996-11E9-8C7C-CF13E6697425
  last_name: Vorlaufer
  orcid: 0009-0000-7590-3501
- 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: Bárbara
  full_name: Oliveira, Bárbara
  id: 3B03AA1A-F248-11E8-B48F-1D18A9856A87
  last_name: Oliveira
- first_name: Alban
  full_name: Cenameri, Alban
  id: 9ac8f577-2357-11eb-997a-e566c5550886
  last_name: Cenameri
- first_name: Gaia
  full_name: Novarino, Gaia
  id: 3E57A680-F248-11E8-B48F-1D18A9856A87
  last_name: Novarino
  orcid: 0000-0002-7673-7178
- first_name: Viren
  full_name: Jain, Viren
  last_name: Jain
- first_name: Johann G
  full_name: Danzl, Johann G
  id: 42EFD3B6-F248-11E8-B48F-1D18A9856A87
  last_name: Danzl
  orcid: 0000-0001-8559-3973
citation:
  ama: Tavakoli M, Lyudchik J, Januszewski M, et al. Light-microscopy-based connectomic
    reconstruction of mammalian brain tissue. <i>Nature</i>. 2025;642:398-410. doi:<a
    href="https://doi.org/10.1038/s41586-025-08985-1">10.1038/s41586-025-08985-1</a>
  apa: Tavakoli, M., Lyudchik, J., Januszewski, M., Vistunou, V., Agudelo Duenas,
    N., Vorlaufer, J., … Danzl, J. G. (2025). Light-microscopy-based connectomic reconstruction
    of mammalian brain tissue. <i>Nature</i>. Springer Nature. <a href="https://doi.org/10.1038/s41586-025-08985-1">https://doi.org/10.1038/s41586-025-08985-1</a>
  chicago: Tavakoli, Mojtaba, Julia Lyudchik, Michał Januszewski, Vitali Vistunou,
    Nathalie Agudelo Duenas, Jakob Vorlaufer, Christoph M Sommer, et al. “Light-Microscopy-Based
    Connectomic Reconstruction of Mammalian Brain Tissue.” <i>Nature</i>. Springer
    Nature, 2025. <a href="https://doi.org/10.1038/s41586-025-08985-1">https://doi.org/10.1038/s41586-025-08985-1</a>.
  ieee: M. Tavakoli <i>et al.</i>, “Light-microscopy-based connectomic reconstruction
    of mammalian brain tissue,” <i>Nature</i>, vol. 642. Springer Nature, pp. 398–410,
    2025.
  ista: Tavakoli M, Lyudchik J, Januszewski M, Vistunou V, Agudelo Duenas N, Vorlaufer
    J, Sommer CM, Kreuzinger C, Oliveira B, Cenameri A, Novarino G, Jain V, Danzl
    JG. 2025. Light-microscopy-based connectomic reconstruction of mammalian brain
    tissue. Nature. 642, 398–410.
  mla: Tavakoli, Mojtaba, et al. “Light-Microscopy-Based Connectomic Reconstruction
    of Mammalian Brain Tissue.” <i>Nature</i>, vol. 642, Springer Nature, 2025, pp.
    398–410, doi:<a href="https://doi.org/10.1038/s41586-025-08985-1">10.1038/s41586-025-08985-1</a>.
  short: M. Tavakoli, J. Lyudchik, M. Januszewski, V. Vistunou, N. Agudelo Duenas,
    J. Vorlaufer, C.M. Sommer, C. Kreuzinger, B. Oliveira, A. Cenameri, G. Novarino,
    V. Jain, J.G. Danzl, Nature 642 (2025) 398–410.
corr_author: '1'
date_created: 2025-05-18T22:02:51Z
date_published: 2025-06-12T00:00:00Z
date_updated: 2026-04-28T13:33:34Z
day: '12'
ddc:
- '570'
department:
- _id: JoDa
- _id: GradSch
- _id: Bio
- _id: GaNo
doi: 10.1038/s41586-025-08985-1
ec_funded: 1
external_id:
  isi:
  - '001483477000001'
  pmid:
  - '40335689'
file:
- access_level: open_access
  checksum: ebc99d7108e728f46db0a009292675ef
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  creator: dernst
  date_created: 2025-07-03T06:55:20Z
  date_updated: 2025-07-03T06:55:20Z
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file_date_updated: 2025-07-03T06:55:20Z
fulldoi: https://doi.org/10.1038/s41586-025-08985-1
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intvolume: '       642'
isi: 1
language:
- iso: eng
month: '06'
oa: 1
oa_version: Published Version
page: 398-410
pmid: 1
project:
- _id: 6285a163-2b32-11ec-9570-8e204ca2dba5
  grant_number: '26137'
  name: Studying Organelle Structure and Function at Nanoscale Resolution with Expansion
    Microscopy
- _id: 2564DBCA-B435-11E9-9278-68D0E5697425
  call_identifier: H2020
  grant_number: '665385'
  name: International IST Doctoral Program
- _id: 34ba8964-11ca-11ed-8bc3-e15864e7e9a6
  grant_number: '101044865'
  name: Toward an understanding of the brain interstitial system and the extracellular
    proteome in health and autism spectrum disorders
- _id: 26AA4EF2-B435-11E9-9278-68D0E5697425
  call_identifier: FWF
  grant_number: W1232-B24
  name: Molecular Drug Targets
publication: Nature
publication_identifier:
  eissn:
  - 1476-4687
  issn:
  - 0028-0836
publication_status: published
publisher: Springer Nature
quality_controlled: '1'
related_material:
  link:
  - description: News on ISTA website
    relation: press_release
    url: https://ista.ac.at/en/news/piecing-together-the-brain-puzzle/
  record:
  - id: '18677'
    relation: earlier_version
    status: public
  - id: '18697'
    relation: research_data
    status: public
scopus_import: '1'
status: public
title: Light-microscopy-based connectomic reconstruction of mammalian brain tissue
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: ba8df636-2132-11f1-aed0-ed93e2281fdd
volume: 642
year: '2025'
...
---
OA_place: repository
_id: '18677'
abstract:
- lang: eng
  text: The information-processing capability of the brain’s cellular network depends
    on the physical wiring pattern between neurons and their molecular and functional
    characteristics. Mapping neurons and resolving their individual synaptic connections
    can be achieved by volumetric imaging at nanoscale resolution with dense cellular
    labeling. Light microscopy is uniquely positioned to visualize specific molecules
    but dense, synapse-level circuit reconstruction by light microscopy has been out
    of reach due to limitations in resolution, contrast, and volumetric imaging capability.
    Here we developed light-microscopy based connectomics (LICONN). We integrated
    specifically engineered hydrogel embedding and expansion with comprehensive deep-learning
    based segmentation and analysis of connectivity, thus directly incorporating molecular
    information in synapse-level brain tissue reconstructions. LICONN will allow synapse-level
    brain tissue phenotyping in biological experiments in a readily adoptable manner.
acknowledged_ssus:
- _id: E-Lib
- _id: M-Shop
- _id: LifeSc
- _id: Bio
- _id: ScienComp
acknowledgement: "We thank Sven Dorkenwald and Peter Li for critical reading of the\r\nmanuscript.
  We acknowledge expert support by ISTA’s scientific service units: Imaging and\r\nOptics,
  Lab Support, Scientific Computing, Preclinical Facility, Miba Machine Shop, and
  Library.\r\nWe gratefully acknowledge funding by the following sources:\r\nAustrian
  Science Fund (FWF) grant DK W1232 (JGD, MRT)\r\nAustrian Academy of Sciences DOC
  fellowship 26137 (MRT)\r\nEU Horizon 2020 program, Marie Skłodowska-Curie Actions
  Fellowship 665385 (JL)\r\nGesellschaft für Forschungsförderung NÖ (NFB) grant LSC18-022
  (JGD)\r\nEuropean Union’s Horizon 2020 research and innovation programme, European
  Research\r\nCouncil (ERC) grant 101044865 “SecretAutism.”\r\n"
article_processing_charge: No
author:
- first_name: Mojtaba
  full_name: Tavakoli, Mojtaba
  id: 3A0A06F4-F248-11E8-B48F-1D18A9856A87
  last_name: Tavakoli
  orcid: 0000-0002-7667-6854
- first_name: Julia
  full_name: Lyudchik, Julia
  id: 46E28B80-F248-11E8-B48F-1D18A9856A87
  last_name: Lyudchik
- first_name: Michał
  full_name: Januszewski, Michał
  last_name: Januszewski
- first_name: Vitali
  full_name: Vistunou, Vitali
  id: 7e146587-8972-11ed-ae7b-d7a32ea86a81
  last_name: Vistunou
- first_name: Nathalie
  full_name: Agudelo Duenas, Nathalie
  id: 40E7F008-F248-11E8-B48F-1D18A9856A87
  last_name: Agudelo Duenas
- first_name: Jakob
  full_name: Vorlaufer, Jakob
  id: 937696FA-C996-11E9-8C7C-CF13E6697425
  last_name: Vorlaufer
  orcid: 0009-0000-7590-3501
- 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: Bárbara
  full_name: Oliveira, Bárbara
  id: 3B03AA1A-F248-11E8-B48F-1D18A9856A87
  last_name: Oliveira
- first_name: Alban
  full_name: Cenameri, Alban
  id: 9ac8f577-2357-11eb-997a-e566c5550886
  last_name: Cenameri
- first_name: Gaia
  full_name: Novarino, Gaia
  id: 3E57A680-F248-11E8-B48F-1D18A9856A87
  last_name: Novarino
  orcid: 0000-0002-7673-7178
- first_name: Viren
  full_name: Jain, Viren
  last_name: Jain
- first_name: Johann G
  full_name: Danzl, Johann G
  id: 42EFD3B6-F248-11E8-B48F-1D18A9856A87
  last_name: Danzl
  orcid: 0000-0001-8559-3973
citation:
  ama: Tavakoli M, Lyudchik J, Januszewski M, et al. Light-microscopy based dense
    connectomic reconstruction of mammalian brain tissue. <i>bioRxiv</i>. doi:<a href="https://doi.org/10.1101/2024.03.01.582884">10.1101/2024.03.01.582884</a>
  apa: Tavakoli, M., Lyudchik, J., Januszewski, M., Vistunou, V., Agudelo Duenas,
    N., Vorlaufer, J., … Danzl, J. G. (n.d.). Light-microscopy based dense connectomic
    reconstruction of mammalian brain tissue. <i>bioRxiv</i>. <a href="https://doi.org/10.1101/2024.03.01.582884">https://doi.org/10.1101/2024.03.01.582884</a>
  chicago: Tavakoli, Mojtaba, Julia Lyudchik, Michał Januszewski, Vitali Vistunou,
    Nathalie Agudelo Duenas, Jakob Vorlaufer, Christoph M Sommer, et al. “Light-Microscopy
    Based Dense Connectomic Reconstruction of Mammalian Brain Tissue.” <i>BioRxiv</i>,
    n.d. <a href="https://doi.org/10.1101/2024.03.01.582884">https://doi.org/10.1101/2024.03.01.582884</a>.
  ieee: M. Tavakoli <i>et al.</i>, “Light-microscopy based dense connectomic reconstruction
    of mammalian brain tissue,” <i>bioRxiv</i>. .
  ista: Tavakoli M, Lyudchik J, Januszewski M, Vistunou V, Agudelo Duenas N, Vorlaufer
    J, Sommer CM, Kreuzinger C, Oliveira B, Cenameri A, Novarino G, Jain V, Danzl
    JG. Light-microscopy based dense connectomic reconstruction of mammalian brain
    tissue. bioRxiv, <a href="https://doi.org/10.1101/2024.03.01.582884">10.1101/2024.03.01.582884</a>.
  mla: Tavakoli, Mojtaba, et al. “Light-Microscopy Based Dense Connectomic Reconstruction
    of Mammalian Brain Tissue.” <i>BioRxiv</i>, doi:<a href="https://doi.org/10.1101/2024.03.01.582884">10.1101/2024.03.01.582884</a>.
  short: M. Tavakoli, J. Lyudchik, M. Januszewski, V. Vistunou, N. Agudelo Duenas,
    J. Vorlaufer, C.M. Sommer, C. Kreuzinger, B. Oliveira, A. Cenameri, G. Novarino,
    V. Jain, J.G. Danzl, BioRxiv (n.d.).
corr_author: '1'
date_created: 2024-12-18T14:48:24Z
date_published: 2024-07-08T00:00:00Z
date_updated: 2026-07-28T08:33:51Z
day: '08'
department:
- _id: GaNo
- _id: JoDa
doi: 10.1101/2024.03.01.582884
ec_funded: 1
fulldoi: https://doi.org/10.1101/2024.03.01.582884
language:
- iso: eng
main_file_link:
- open_access: '1'
  url: https://doi.org/10.1101/2024.03.01.582884
month: '07'
oa: 1
oa_version: Preprint
project:
- _id: 6285a163-2b32-11ec-9570-8e204ca2dba5
  grant_number: '26137'
  name: Studying Organelle Structure and Function at Nanoscale Resolution with Expansion
    Microscopy
- _id: 2564DBCA-B435-11E9-9278-68D0E5697425
  call_identifier: H2020
  grant_number: '665385'
  name: International IST Doctoral Program
- _id: 34ba8964-11ca-11ed-8bc3-e15864e7e9a6
  grant_number: '101044865'
  name: Toward an understanding of the brain interstitial system and the extracellular
    proteome in health and autism spectrum disorders
- _id: 26AA4EF2-B435-11E9-9278-68D0E5697425
  call_identifier: FWF
  grant_number: W1232-B24
  name: Molecular Drug Targets
publication: bioRxiv
publication_status: draft
related_material:
  record:
  - id: '18674'
    relation: dissertation_contains
    status: public
  - id: '19704'
    relation: later_version
    status: public
  - id: '18681'
    relation: dissertation_contains
    status: public
status: public
title: Light-microscopy based dense connectomic reconstruction of mammalian brain
  tissue
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: '2024'
...
---
_id: '11160'
abstract:
- lang: eng
  text: Mutations in the chromodomain helicase DNA-binding 8 (CHD8) gene are a frequent
    cause of autism spectrum disorder (ASD). While its phenotypic spectrum often encompasses
    macrocephaly, implicating cortical abnormalities, how CHD8 haploinsufficiency
    affects neurodevelopmental is unclear. Here, employing human cerebral organoids,
    we find that CHD8 haploinsufficiency disrupted neurodevelopmental trajectories
    with an accelerated and delayed generation of, respectively, inhibitory and excitatory
    neurons that yields, at days 60 and 120, symmetrically opposite expansions in
    their proportions. This imbalance is consistent with an enlargement of cerebral
    organoids as an in vitro correlate of patients’ macrocephaly. Through an isogenic
    design of patient-specific mutations and mosaic organoids, we define genotype-phenotype
    relationships and uncover their cell-autonomous nature. Our results define cell-type-specific
    CHD8-dependent molecular defects related to an abnormal program of proliferation
    and alternative splicing. By identifying cell-type-specific effects of CHD8 mutations,
    our study uncovers reproducible developmental alterations that may be employed
    for neurodevelopmental disease modeling.
acknowledged_ssus:
- _id: Bio
- _id: LifeSc
acknowledgement: We thank Farnaz Freeman for technical assistance. This research was
  supported by the Scientific Service Units (SSU) of IST Austria through resources
  provided by the Bioimaging Facility (BIF) and the Life Science Facility (LSF). This
  work supported by the European Union’s Horizon 2020 research and innovation program
  (ERC) grant 715508 to G.N. (REVERSEAUTISM) and grant 825759 to G.T. (ENDpoiNTs);
  the Fondazione Cariplo 2017-0886 to A.L.T.; E-Rare-3 JTC 2018 IMPACT to M. Gabriele;
  and the Austrian Science Fund FWF I 4205-B to G.N. Graphical abstract and figures
  were created using BioRender.com.
article_number: '110615'
article_processing_charge: Yes
article_type: original
author:
- first_name: Carlo Emanuele
  full_name: Villa, Carlo Emanuele
  last_name: Villa
- first_name: Cristina
  full_name: Cheroni, Cristina
  last_name: Cheroni
- first_name: Christoph
  full_name: Dotter, Christoph
  id: 4C66542E-F248-11E8-B48F-1D18A9856A87
  last_name: Dotter
  orcid: 0000-0002-9033-9096
- first_name: Alejandro
  full_name: López-Tóbon, Alejandro
  last_name: López-Tóbon
- first_name: Bárbara
  full_name: Oliveira, Bárbara
  id: 3B03AA1A-F248-11E8-B48F-1D18A9856A87
  last_name: Oliveira
- first_name: Roberto
  full_name: Sacco, Roberto
  id: 42C9F57E-F248-11E8-B48F-1D18A9856A87
  last_name: Sacco
- first_name: Aysan Çerağ
  full_name: Yahya, Aysan Çerağ
  id: 365A65F8-F248-11E8-B48F-1D18A9856A87
  last_name: Yahya
- first_name: Jasmin
  full_name: Morandell, Jasmin
  id: 4739D480-F248-11E8-B48F-1D18A9856A87
  last_name: Morandell
- first_name: Michele
  full_name: Gabriele, Michele
  last_name: Gabriele
- first_name: Mojtaba
  full_name: Tavakoli, Mojtaba
  id: 3A0A06F4-F248-11E8-B48F-1D18A9856A87
  last_name: Tavakoli
  orcid: 0000-0002-7667-6854
- first_name: Julia
  full_name: Lyudchik, Julia
  id: 46E28B80-F248-11E8-B48F-1D18A9856A87
  last_name: Lyudchik
- 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: Mariano
  full_name: Gabitto, Mariano
  last_name: Gabitto
- 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: Giuseppe
  full_name: Testa, Giuseppe
  last_name: Testa
- first_name: Gaia
  full_name: Novarino, Gaia
  id: 3E57A680-F248-11E8-B48F-1D18A9856A87
  last_name: Novarino
  orcid: 0000-0002-7673-7178
citation:
  ama: Villa CE, Cheroni C, Dotter C, et al. CHD8 haploinsufficiency links autism
    to transient alterations in excitatory and inhibitory trajectories. <i>Cell Reports</i>.
    2022;39(1). doi:<a href="https://doi.org/10.1016/j.celrep.2022.110615">10.1016/j.celrep.2022.110615</a>
  apa: Villa, C. E., Cheroni, C., Dotter, C., López-Tóbon, A., Oliveira, B., Sacco,
    R., … Novarino, G. (2022). CHD8 haploinsufficiency links autism to transient alterations
    in excitatory and inhibitory trajectories. <i>Cell Reports</i>. Elsevier. <a href="https://doi.org/10.1016/j.celrep.2022.110615">https://doi.org/10.1016/j.celrep.2022.110615</a>
  chicago: Villa, Carlo Emanuele, Cristina Cheroni, Christoph Dotter, Alejandro López-Tóbon,
    Bárbara Oliveira, Roberto Sacco, Aysan Çerağ Yahya, et al. “CHD8 Haploinsufficiency
    Links Autism to Transient Alterations in Excitatory and Inhibitory Trajectories.”
    <i>Cell Reports</i>. Elsevier, 2022. <a href="https://doi.org/10.1016/j.celrep.2022.110615">https://doi.org/10.1016/j.celrep.2022.110615</a>.
  ieee: C. E. Villa <i>et al.</i>, “CHD8 haploinsufficiency links autism to transient
    alterations in excitatory and inhibitory trajectories,” <i>Cell Reports</i>, vol.
    39, no. 1. Elsevier, 2022.
  ista: Villa CE, Cheroni C, Dotter C, López-Tóbon A, Oliveira B, Sacco R, Yahya AÇ,
    Morandell J, Gabriele M, Tavakoli M, Lyudchik J, Sommer CM, Gabitto M, Danzl JG,
    Testa G, Novarino G. 2022. CHD8 haploinsufficiency links autism to transient alterations
    in excitatory and inhibitory trajectories. Cell Reports. 39(1), 110615.
  mla: Villa, Carlo Emanuele, et al. “CHD8 Haploinsufficiency Links Autism to Transient
    Alterations in Excitatory and Inhibitory Trajectories.” <i>Cell Reports</i>, vol.
    39, no. 1, 110615, Elsevier, 2022, doi:<a href="https://doi.org/10.1016/j.celrep.2022.110615">10.1016/j.celrep.2022.110615</a>.
  short: C.E. Villa, C. Cheroni, C. Dotter, A. López-Tóbon, B. Oliveira, R. Sacco,
    A.Ç. Yahya, J. Morandell, M. Gabriele, M. Tavakoli, J. Lyudchik, C.M. Sommer,
    M. Gabitto, J.G. Danzl, G. Testa, G. Novarino, Cell Reports 39 (2022).
corr_author: '1'
date_created: 2022-04-15T09:03:10Z
date_published: 2022-04-05T00:00:00Z
date_updated: 2026-09-23T22:30:06Z
day: '05'
ddc:
- '570'
department:
- _id: JoDa
- _id: GaNo
doi: 10.1016/j.celrep.2022.110615
ec_funded: 1
external_id:
  isi:
  - '000785983900003'
  pmid:
  - '35385734'
file:
- access_level: open_access
  checksum: b4e8d68f0268dec499af333e6fd5d8e1
  content_type: application/pdf
  creator: dernst
  date_created: 2022-04-15T09:06:25Z
  date_updated: 2022-04-15T09:06:25Z
  file_id: '11164'
  file_name: 2022_CellReports_Villa.pdf
  file_size: '7808644'
  relation: main_file
  success: 1
file_date_updated: 2022-04-15T09:06:25Z
fulldoi: https://doi.org/10.1016/j.celrep.2022.110615
has_accepted_license: '1'
intvolume: '        39'
isi: 1
issue: '1'
keyword:
- General Biochemistry
- Genetics and Molecular Biology
language:
- iso: eng
month: '04'
oa: 1
oa_version: Published Version
pmid: 1
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: 2690FEAC-B435-11E9-9278-68D0E5697425
  call_identifier: FWF
  grant_number: I04205
  name: Identification of converging Molecular Pathways Across Chromatinopathies as
    Targets for Therapy
publication: Cell Reports
publication_identifier:
  issn:
  - 2211-1247
publication_status: published
publisher: Elsevier
quality_controlled: '1'
related_material:
  record:
  - id: '18674'
    relation: dissertation_contains
    status: public
  - id: '18681'
    relation: dissertation_contains
    status: public
  - id: '12364'
    relation: dissertation_contains
    status: public
scopus_import: '1'
status: public
title: CHD8 haploinsufficiency links autism to transient alterations in excitatory
  and inhibitory trajectories
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: 3E5EF7F0-F248-11E8-B48F-1D18A9856A87
volume: 39
year: '2022'
...
---
_id: '6896'
abstract:
- lang: eng
  text: "Until recently, a great amount of brain studies have been conducted in human
    post mortem tissues, cell lines and model organisms. These researches provided
    useful insights regarding cell-cell interactions occurring in the brain. However,
    such approaches suffer from technical limitations and inaccurate modeling of the
    tissue 3D cytoarchitecture. Importantly, they might lack a human genetic background
    essential for disease modeling. With the development of protocols to generate
    human cerebral organoids, we are now closer to reproducing the early stages of
    human brain development in vitro. As a result, more relevant cell-cell interaction
    studies can be conducted.\r\n\r\nIn this review, we discuss the advantages of
    3D cultures over 2D in modulating brain cell-cell interactions during physiological
    and pathological development, as well as the progress made in developing organoids
    in which neurons, macroglia, microglia and vascularization are present. Finally,
    we debate the limitations of those models and possible future directions."
article_number: '146458'
article_processing_charge: No
article_type: original
author:
- first_name: Bárbara
  full_name: Oliveira, Bárbara
  id: 3B03AA1A-F248-11E8-B48F-1D18A9856A87
  last_name: Oliveira
- first_name: Aysan Çerağ
  full_name: Yahya, Aysan Çerağ
  id: 365A65F8-F248-11E8-B48F-1D18A9856A87
  last_name: Yahya
- first_name: Gaia
  full_name: Novarino, Gaia
  id: 3E57A680-F248-11E8-B48F-1D18A9856A87
  last_name: Novarino
  orcid: 0000-0002-7673-7178
citation:
  ama: Oliveira B, Yahya AÇ, Novarino G. Modeling cell-cell interactions in the brain
    using cerebral organoids. <i>Brain Research</i>. 2019;1724. doi:<a href="https://doi.org/10.1016/j.brainres.2019.146458">10.1016/j.brainres.2019.146458</a>
  apa: Oliveira, B., Yahya, A. Ç., &#38; Novarino, G. (2019). Modeling cell-cell interactions
    in the brain using cerebral organoids. <i>Brain Research</i>. Elsevier. <a href="https://doi.org/10.1016/j.brainres.2019.146458">https://doi.org/10.1016/j.brainres.2019.146458</a>
  chicago: Oliveira, Bárbara, Aysan Çerağ Yahya, and Gaia Novarino. “Modeling Cell-Cell
    Interactions in the Brain Using Cerebral Organoids.” <i>Brain Research</i>. Elsevier,
    2019. <a href="https://doi.org/10.1016/j.brainres.2019.146458">https://doi.org/10.1016/j.brainres.2019.146458</a>.
  ieee: B. Oliveira, A. Ç. Yahya, and G. Novarino, “Modeling cell-cell interactions
    in the brain using cerebral organoids,” <i>Brain Research</i>, vol. 1724. Elsevier,
    2019.
  ista: Oliveira B, Yahya AÇ, Novarino G. 2019. Modeling cell-cell interactions in
    the brain using cerebral organoids. Brain Research. 1724, 146458.
  mla: Oliveira, Bárbara, et al. “Modeling Cell-Cell Interactions in the Brain Using
    Cerebral Organoids.” <i>Brain Research</i>, vol. 1724, 146458, Elsevier, 2019,
    doi:<a href="https://doi.org/10.1016/j.brainres.2019.146458">10.1016/j.brainres.2019.146458</a>.
  short: B. Oliveira, A.Ç. Yahya, G. Novarino, Brain Research 1724 (2019).
date_created: 2019-09-22T22:00:35Z
date_published: 2019-12-01T00:00:00Z
date_updated: 2025-07-10T11:54:01Z
day: '01'
department:
- _id: GaNo
doi: 10.1016/j.brainres.2019.146458
external_id:
  isi:
  - '000491646600033'
  pmid:
  - '31521639'
fulldoi: https://doi.org/10.1016/j.brainres.2019.146458
intvolume: '      1724'
isi: 1
language:
- iso: eng
month: '12'
oa_version: None
pmid: 1
publication: Brain Research
publication_identifier:
  eissn:
  - 1872-6240
  issn:
  - 0006-8993
publication_status: published
publisher: Elsevier
quality_controlled: '1'
scopus_import: '1'
status: public
title: Modeling cell-cell interactions in the brain using cerebral organoids
type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 1724
year: '2019'
...