---
_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).
date_created: 2022-04-15T09:03:10Z
date_published: 2022-04-05T00:00:00Z
date_updated: 2024-03-25T23:30:25Z
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
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: '12364'
    relation: dissertation_contains
    status: public
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: 2023-08-30T06:19:49Z
day: '01'
department:
- _id: GaNo
doi: 10.1016/j.brainres.2019.146458
external_id:
  isi:
  - '000491646600033'
  pmid:
  - '31521639'
intvolume: '      1724'
isi: 1
language:
- iso: eng
month: '12'
oa_version: None
pmid: 1
publication: Brain Research
publication_identifier:
  eissn:
  - '18726240'
  issn:
  - '00068993'
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: 4359f0d1-fa6c-11eb-b949-802e58b17ae8
volume: 1724
year: '2019'
...