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Cited by 27Neurogenesis and neuroplasticity mechanismsDown syndrome and intellectual disability researchPluripotent Stem Cells Research

Sonic Hedgehog Pathway Modulation Normalizes Expression of Olig2 in Rostrally Patterned NPCs With Trisomy 21

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Klein, Jenny A., Li, Zhen, Rampam, Sanjeev, Cardini, Jack, Ayoub, Amara, Shaw, Patricia, Rachubinski, Angela L., Espinosa, Joaquin M. +2 more·2022·Frontiers in Cellular Neuroscience
DOI 10.3389/fncel.2021.794675PMC PMC8763807

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Abstract

The intellectual disability found in people with Down syndrome is associated with numerous changes in early brain development, including the proliferation and differentiation of neural progenitor cells (NPCs) and the formation and maintenance of myelin in the brain. To study how early neural precursors are affected by trisomy 21, we differentiated two isogenic lines of induced pluripotent stem cells derived from people with Down syndrome into brain-like and spinal cord-like NPCs and promoted a transition towards oligodendroglial fate by activating the Sonic hedgehog (SHH) pathway. In the spinal cord-like trisomic cells, we found no difference in expression of OLIG2 or NKX2.2, two transcription factors essential for commitment to the oligodendrocyte lineage. However, in the brain-like trisomic NPCs, OLIG2 is significantly upregulated and is associated with reduced expression of NKX2.2. We found that this gene dysregulation and block in NPC transition can be normalized by increasing the concentration of a SHH pathway agonist (SAG) during differentiation. These results underscore the importance of regional and cell type differences in gene expression in Down syndrome and demonstrate that modulation of SHH signaling in trisomic cells can rescue an early perturbed step in neural lineage specification.

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  • A few studies indicate that increased proportions of OLIG2-expressing progenitor cells are produced by trisomy 21 induced pluripotent stem cells differentiated in both two-dimensional and three-dimensional cultures, compared to controls.

    “Nonetheless, a few studies indicate that increased proportions of OLIG2-expressing progenitor cells are produced by T21 iPSCs differentiated in both two-dimensional and three-dimensional cultures, compared to controls73,91.”

    From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [73]

    The Results section, “Rostral Patterned tNPCs Show an Altered Response to SHH Activation” (page unavailable), reports higher proportions of OLIG2-positive progenitors in trisomic than euploid iPSC-derived cultures. The paper’s Methods describe cells grown in culture wells, but our copy does not report the claimed increase in a three-dimensional culture; the cited sentence does not specify which of its two references supports that part. (LLM, conf=0.85)

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  • In 2D culture, there is an increase in OLIG2 expressing ventral NPCs.

    “This increase in percentage of OLIG2 expressing ventral NPCs was also found in two dimensional culture where two isogenic lines of iPSCs were differentiated to brain-like NPCs and ventralized (Klein et al., 2022).”

    From Neurodevelopment in Down syndrome: Concordance in humans and models (2022) · cites this paper as Klein et al., 2022

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Authors
Klein, J. A., Li, Z., Rampam, S., Cardini, J., Ayoub, A., Shaw, P., Rachubinski, A. L., Espinosa, J. M., Zeldich, E., & Haydar, T. F.
Affiliations
  • Boston University (US)
  • Children's National (US)
  • University of Colorado Anschutz (US)
Corresponding author
  • Zeldich, Ella
  • Haydar, Tarik F.
ORCID
Venue
Frontiers in Cellular Neuroscience
Publisher
Frontiers Media SA
Published
2022-01-04
Volume
15
Pages
794675-794675
ISSN
1662-5102 (ISSN-L)
DOI
10.3389/fncel.2021.794675
PMC
PMC8763807
OpenAlex
W4226027615
Cited by
27
References
66
Citations by year
2026: 6 · 2025: 3 · 2024: 7 · 2023: 8 · 2022: 3
FWCI
1.92
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Cellular Neuroscience (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Global Down Syndrome Foundation
  • National Institutes of Health
  • Anschutz Medical Campus, University of Colorado
  • National Institute of Neurological Disorders and Stroke (R21-HD098542)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (R21HD098542)
  • Linda Crnic Institute for Down Syndrome, University of Colorado School of Medicine, Anschutz Medical Campus
Topics
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
Keywords
Down syndrome, Sonic hedgehog signaling, Olig2, Nkx2.2, neural progenitor cells, induced pluripotent stem cells, intellectual disability, brain development, spinal cord, myelination

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