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Article: Organoid models of breathing disorders reveal patterning defect of hindbrain neurons caused by PHOX2B-PARMs

TitleOrganoid models of breathing disorders reveal patterning defect of hindbrain neurons caused by PHOX2B-PARMs
Authors
KeywordsBreathing disorder
carbon dioxide (CO2)-sensitive glutamatergic neurons
Congenital central hypoventilation syndrome
Human brainstem organoids
Human cerebral organoids
Human pluripotent stem cells
PHOX2B
PHOX2B-PARMs
Retrotrapezoid nucleus (RTN) neurons
Issue Date11-Jul-2023
PublisherCell Press
Citation
Stem Cell Reports, 2023, v. 18, n. 7, p. 1500-1515 How to Cite?
Abstract

Retrotrapezoid nucleus (RTN) neurons in the brainstem regulate the ventilatory response to hypercarbia. It is unclear how PHOX2B-polyalanine repeat mutations (PHOX2B-PARMs) alter the function of PHOX2B and perturb the formation of RTN neurons. Here, we generated human brainstem organoids (HBSOs) with RTN-like neurons from human pluripotent stem cells. Single-cell transcriptomics revealed that expression of PHOX2B+7Ala PARM alters the differentiation trajectories of the hindbrain neurons and hampers the formation of the RTN-like neurons in HBSOs. With the unguided cerebral organoids (HCOs), PHOX2B+7Ala PARM interrupted the patterning of PHOX2B+ neurons with dysregulation of Hedgehog pathway and HOX genes. With complementary use of HBSOs and HCOs with a patient and two mutant induced pluripotent stem cell lines carrying different polyalanine repetition in PHOX2B, we further defined the association between the length of polyalanine repetition and malformation of RTN-respiratory center and demonstrated the potential toxic gain of function of PHOX2B-PARMs, highlighting the uniqueness of these organoid models for disease modeling.


Persistent Identifierhttp://hdl.handle.net/10722/340843
ISSN
2023 Impact Factor: 5.9
2023 SCImago Journal Rankings: 2.518
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorLui, KNC-
dc.contributor.authorLi, ZX-
dc.contributor.authorLai, FPL-
dc.contributor.authorLau, ST-
dc.contributor.authorNgan, ESW-
dc.date.accessioned2024-03-11T10:47:43Z-
dc.date.available2024-03-11T10:47:43Z-
dc.date.issued2023-07-11-
dc.identifier.citationStem Cell Reports, 2023, v. 18, n. 7, p. 1500-1515-
dc.identifier.issn2213-6711-
dc.identifier.urihttp://hdl.handle.net/10722/340843-
dc.description.abstract<p> Retrotrapezoid nucleus (RTN) neurons in the brainstem regulate the ventilatory response to hypercarbia. It is unclear how PHOX2B-polyalanine repeat mutations (PHOX2B-PARMs) alter the function of PHOX2B and perturb the formation of RTN neurons. Here, we generated human brainstem organoids (HBSOs) with RTN-like neurons from human pluripotent stem cells. Single-cell transcriptomics revealed that expression of PHOX2B+7Ala PARM alters the differentiation trajectories of the hindbrain neurons and hampers the formation of the RTN-like neurons in HBSOs. With the unguided cerebral organoids (HCOs), PHOX2B+7Ala PARM interrupted the patterning of PHOX2B+ neurons with dysregulation of Hedgehog pathway and HOX genes. With complementary use of HBSOs and HCOs with a patient and two mutant induced pluripotent stem cell lines carrying different polyalanine repetition in PHOX2B, we further defined the association between the length of polyalanine repetition and malformation of RTN-respiratory center and demonstrated the potential toxic gain of function of PHOX2B-PARMs, highlighting the uniqueness of these organoid models for disease modeling. <br></p>-
dc.languageeng-
dc.publisherCell Press-
dc.relation.ispartofStem Cell Reports-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectBreathing disorder-
dc.subjectcarbon dioxide (CO2)-sensitive glutamatergic neurons-
dc.subjectCongenital central hypoventilation syndrome-
dc.subjectHuman brainstem organoids-
dc.subjectHuman cerebral organoids-
dc.subjectHuman pluripotent stem cells-
dc.subjectPHOX2B-
dc.subjectPHOX2B-PARMs-
dc.subjectRetrotrapezoid nucleus (RTN) neurons-
dc.titleOrganoid models of breathing disorders reveal patterning defect of hindbrain neurons caused by PHOX2B-PARMs-
dc.typeArticle-
dc.description.naturepreprint-
dc.identifier.doi10.1016/j.stemcr.2023.05.020-
dc.identifier.scopuseid_2-s2.0-85164311695-
dc.identifier.volume18-
dc.identifier.issue7-
dc.identifier.spage1500-
dc.identifier.epage1515-
dc.identifier.eissn2213-6711-
dc.identifier.isiWOS:001047997200001-
dc.identifier.issnl2213-6711-

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