---
_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:
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  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: '7128'
abstract:
- lang: eng
  text: Loss of functional cardiomyocytes is a major determinant of heart failure
    after myocardial infarction. Previous high throughput screening studies have identified
    a few microRNAs (miRNAs) that can induce cardiomyocyte proliferation and stimulate
    cardiac regeneration in mice. Here, we show that all of the most effective of
    these miRNAs activate nuclear localization of the master transcriptional cofactor
    Yes-associated protein (YAP) and induce expression of YAP-responsive genes. In
    particular, miR-199a-3p directly targets two mRNAs coding for proteins impinging
    on the Hippo pathway, the upstream YAP inhibitory kinase TAOK1, and the E3 ubiquitin
    ligase β-TrCP, which leads to YAP degradation. Several of the pro-proliferative
    miRNAs (including miR-199a-3p) also inhibit filamentous actin depolymerization
    by targeting Cofilin2, a process that by itself activates YAP nuclear translocation.
    Thus, activation of YAP and modulation of the actin cytoskeleton are major components
    of the pro-proliferative action of miR-199a-3p and other miRNAs that induce cardiomyocyte
    proliferation.
article_processing_charge: Yes
article_type: original
author:
- first_name: Consuelo
  full_name: Torrini, Consuelo
  last_name: Torrini
- first_name: Ryan J
  full_name: Cubero, Ryan J
  id: 850B2E12-9CD4-11E9-837F-E719E6697425
  last_name: Cubero
  orcid: 0000-0003-0002-1867
- first_name: Ellen
  full_name: Dirkx, Ellen
  last_name: Dirkx
- first_name: Luca
  full_name: Braga, Luca
  last_name: Braga
- first_name: Hashim
  full_name: Ali, Hashim
  last_name: Ali
- first_name: Giulia
  full_name: Prosdocimo, Giulia
  last_name: Prosdocimo
- first_name: Maria Ines
  full_name: Gutierrez, Maria Ines
  last_name: Gutierrez
- first_name: Chiara
  full_name: Collesi, Chiara
  last_name: Collesi
- first_name: Danilo
  full_name: Licastro, Danilo
  last_name: Licastro
- first_name: Lorena
  full_name: Zentilin, Lorena
  last_name: Zentilin
- first_name: Miguel
  full_name: Mano, Miguel
  last_name: Mano
- first_name: Serena
  full_name: Zacchigna, Serena
  last_name: Zacchigna
- first_name: Michele
  full_name: Vendruscolo, Michele
  last_name: Vendruscolo
- first_name: Matteo
  full_name: Marsili, Matteo
  last_name: Marsili
- first_name: Areejit
  full_name: Samal, Areejit
  last_name: Samal
- first_name: Mauro
  full_name: Giacca, Mauro
  last_name: Giacca
citation:
  ama: Torrini C, Cubero RJ, Dirkx E, et al. Common regulatory pathways mediate activity
    of microRNAs inducing cardiomyocyte proliferation. <i>Cell Reports</i>. 2019;27(9):2759-2771.e5.
    doi:<a href="https://doi.org/10.1016/j.celrep.2019.05.005">10.1016/j.celrep.2019.05.005</a>
  apa: Torrini, C., Cubero, R. J., Dirkx, E., Braga, L., Ali, H., Prosdocimo, G.,
    … Giacca, M. (2019). Common regulatory pathways mediate activity of microRNAs
    inducing cardiomyocyte proliferation. <i>Cell Reports</i>. Elsevier. <a href="https://doi.org/10.1016/j.celrep.2019.05.005">https://doi.org/10.1016/j.celrep.2019.05.005</a>
  chicago: Torrini, Consuelo, Ryan J Cubero, Ellen Dirkx, Luca Braga, Hashim Ali,
    Giulia Prosdocimo, Maria Ines Gutierrez, et al. “Common Regulatory Pathways Mediate
    Activity of MicroRNAs Inducing Cardiomyocyte Proliferation.” <i>Cell Reports</i>.
    Elsevier, 2019. <a href="https://doi.org/10.1016/j.celrep.2019.05.005">https://doi.org/10.1016/j.celrep.2019.05.005</a>.
  ieee: C. Torrini <i>et al.</i>, “Common regulatory pathways mediate activity of
    microRNAs inducing cardiomyocyte proliferation,” <i>Cell Reports</i>, vol. 27,
    no. 9. Elsevier, p. 2759–2771.e5, 2019.
  ista: Torrini C, Cubero RJ, Dirkx E, Braga L, Ali H, Prosdocimo G, Gutierrez MI,
    Collesi C, Licastro D, Zentilin L, Mano M, Zacchigna S, Vendruscolo M, Marsili
    M, Samal A, Giacca M. 2019. Common regulatory pathways mediate activity of microRNAs
    inducing cardiomyocyte proliferation. Cell Reports. 27(9), 2759–2771.e5.
  mla: Torrini, Consuelo, et al. “Common Regulatory Pathways Mediate Activity of MicroRNAs
    Inducing Cardiomyocyte Proliferation.” <i>Cell Reports</i>, vol. 27, no. 9, Elsevier,
    2019, p. 2759–2771.e5, doi:<a href="https://doi.org/10.1016/j.celrep.2019.05.005">10.1016/j.celrep.2019.05.005</a>.
  short: C. Torrini, R.J. Cubero, E. Dirkx, L. Braga, H. Ali, G. Prosdocimo, M.I.
    Gutierrez, C. Collesi, D. Licastro, L. Zentilin, M. Mano, S. Zacchigna, M. Vendruscolo,
    M. Marsili, A. Samal, M. Giacca, Cell Reports 27 (2019) 2759–2771.e5.
date_created: 2019-11-26T22:30:07Z
date_published: 2019-05-28T00:00:00Z
date_updated: 2021-01-12T08:11:56Z
day: '28'
ddc:
- '576'
doi: 10.1016/j.celrep.2019.05.005
extern: '1'
external_id:
  pmid:
  - '31141697'
file:
- access_level: open_access
  checksum: c5d855d07263bfec718673385d0ea2d7
  content_type: application/pdf
  creator: rcubero
  date_created: 2019-11-26T22:30:43Z
  date_updated: 2020-07-14T12:47:50Z
  file_id: '7129'
  file_name: torrini_cellreports_2019.pdf
  file_size: 4650750
  relation: main_file
file_date_updated: 2020-07-14T12:47:50Z
has_accepted_license: '1'
intvolume: '        27'
issue: '9'
keyword:
- cardiomyocyte
- cell cycle
- Cofilin2
- cytoskeleton
- Hippo
- microRNA
- regeneration
- YAP
language:
- iso: eng
month: '05'
oa: 1
oa_version: Published Version
page: 2759-2771.e5
pmid: 1
publication: Cell Reports
publication_identifier:
  issn:
  - 2211-1247
publication_status: published
publisher: Elsevier
quality_controlled: '1'
status: public
title: Common regulatory pathways mediate activity of microRNAs inducing cardiomyocyte
  proliferation
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: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 27
year: '2019'
...
---
_id: '7598'
article_processing_charge: No
article_type: original
author:
- first_name: Shutang
  full_name: Tan, Shutang
  id: 2DE75584-F248-11E8-B48F-1D18A9856A87
  last_name: Tan
  orcid: 0000-0002-0471-8285
- first_name: Hong-Wei
  full_name: Xue, Hong-Wei
  last_name: Xue
citation:
  ama: Tan S, Xue H-W. Casein kinase 1 regulates ethylene synthesis by phosphorylating
    and promoting the turnover of ACS5. <i>Cell Reports</i>. 2014;9(5):1692-1702.
    doi:<a href="https://doi.org/10.1016/j.celrep.2014.10.047">10.1016/j.celrep.2014.10.047</a>
  apa: Tan, S., &#38; Xue, H.-W. (2014). Casein kinase 1 regulates ethylene synthesis
    by phosphorylating and promoting the turnover of ACS5. <i>Cell Reports</i>. Elsevier.
    <a href="https://doi.org/10.1016/j.celrep.2014.10.047">https://doi.org/10.1016/j.celrep.2014.10.047</a>
  chicago: Tan, Shutang, and Hong-Wei Xue. “Casein Kinase 1 Regulates Ethylene Synthesis
    by Phosphorylating and Promoting the Turnover of ACS5.” <i>Cell Reports</i>. Elsevier,
    2014. <a href="https://doi.org/10.1016/j.celrep.2014.10.047">https://doi.org/10.1016/j.celrep.2014.10.047</a>.
  ieee: S. Tan and H.-W. Xue, “Casein kinase 1 regulates ethylene synthesis by phosphorylating
    and promoting the turnover of ACS5,” <i>Cell Reports</i>, vol. 9, no. 5. Elsevier,
    pp. 1692–1702, 2014.
  ista: Tan S, Xue H-W. 2014. Casein kinase 1 regulates ethylene synthesis by phosphorylating
    and promoting the turnover of ACS5. Cell Reports. 9(5), 1692–1702.
  mla: Tan, Shutang, and Hong-Wei Xue. “Casein Kinase 1 Regulates Ethylene Synthesis
    by Phosphorylating and Promoting the Turnover of ACS5.” <i>Cell Reports</i>, vol.
    9, no. 5, Elsevier, 2014, pp. 1692–702, doi:<a href="https://doi.org/10.1016/j.celrep.2014.10.047">10.1016/j.celrep.2014.10.047</a>.
  short: S. Tan, H.-W. Xue, Cell Reports 9 (2014) 1692–1702.
date_created: 2020-03-21T16:08:18Z
date_published: 2014-12-11T00:00:00Z
date_updated: 2021-01-12T08:14:24Z
day: '11'
ddc:
- '580'
doi: 10.1016/j.celrep.2014.10.047
extern: '1'
file:
- access_level: open_access
  checksum: 23c30de4ac98ce9879fc054121517626
  content_type: application/pdf
  creator: dernst
  date_created: 2020-03-23T12:23:40Z
  date_updated: 2020-07-14T12:48:01Z
  file_id: '7613'
  file_name: 2014_CellPress_Tan.pdf
  file_size: 2755808
  relation: main_file
file_date_updated: 2020-07-14T12:48:01Z
has_accepted_license: '1'
intvolume: '         9'
issue: '5'
language:
- iso: eng
month: '12'
oa: 1
oa_version: Published Version
page: 1692-1702
publication: Cell Reports
publication_identifier:
  issn:
  - 2211-1247
publication_status: published
publisher: Elsevier
quality_controlled: '1'
status: public
title: Casein kinase 1 regulates ethylene synthesis by phosphorylating and promoting
  the turnover of ACS5
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: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 9
year: '2014'
...