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Cited by 200Down syndrome and intellectual disability researchGenetics and Neurodevelopmental DisordersNeurogenesis and neuroplasticity mechanisms

Trisomy 21 and early brain development

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Haydar, Tarik F., Reeves, Roger H.·2012·Trends in Neurosciences
DOI 10.1016/j.tins.2011.11.001PMC PMC3273608
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Abstract

Trisomy for human chromosome 21 (Hsa21) results in Down syndrome (DS). The finished human genome sequence provides a thorough catalog of the genetic elements whose altered dosage perturbs development and function in DS. However, understanding how small alterations in the steady state transcript levels for <2% of human genes can disrupt development and function of essentially every cell presents a more complicated problem. Mouse models that recapitulate specific aspects of DS have been used to identify changes in brain morphogenesis and function. Here we provide a few examples of how trisomy for specific genes affects the development of the cortex and cerebellum to illustrate how gene dosage effects might contribute to divergence between the trisomic and euploid brains.

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  • There is substantial evidence of neuropathology from early in life in DS, including defects in neuronal development, increased ratio of inhibitory to excitatory neurons, alterations in neuronal dendritic spine dynamics, activation of microglia, astrocyte reactivity, and elevated production of inflammatory cytokines in the brain.

    “There is substantial evidence of neuropathology from early in life in DS,6,9,10,21 including defects in neuronal development, an increased ratio of inhibitory to excitatory neurons, alterations in neuronal dendritic spines dynamics, activation of microglia, astrocyte reactivity, and elevated production of inflammatory cytokines in the brain.22,23,24,25”

    From Interferon signaling modulates Down syndrome-associated Alzheimer’s disease pathology in a mouse model (2025) · cites this paper as [23]

    Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

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  • Overexpression of DYRK1A is hypothesized to cause cell cycle dysregulation in mouse models of DS, including at the G1/S phase.

    “an overexpression of DYRK1A (observed in the current study) is hypothesized to cause cell cycle dysregulation in mouse models of DS (Haydar and Reeves, 2012) including the G1/S phase”

    From Sex-specific developmental alterations in DYRK1A expression in the brain of a Down syndrome mouse model (2024) · cites this paper as Haydar and Reeves, 2012

    In “The dorsal forebrain phenotype: under-production of excitatory neurons” (page not provided), the paper says DYRK1A is triplicated in DS and several mouse models, and reports that Dyrk1a overexpression inhibits neural-precursor proliferation and promotes premature differentiation. It links this effect partly to Cyclin D1 degradation, but does not specifically identify dysregulation at the G1/S phase. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Mouse models have allowed advances in deciphering mechanisms governing brain development and function and the consequences of Down syndrome-related manipulations.

    “These models have allowed the scientific community to make incredible advances in deciphering the mechanisms governing brain development and function, as well as the consequences of DS-related manipulations for those mechanisms18–22.”

    From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [22]

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References 126 · Cited by 200

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Authors
Haydar, T. F., & Reeves, R. H.
Affiliations
  • Boston University (US)
  • Johns Hopkins University (US)
Corresponding author
  • Haydar, Tarik F.
  • Reeves, Roger H.
ORCID
Venue
Trends in Neurosciences
Publisher
Elsevier BV
Published
2012-02
Volume
35
Issue
2
Pages
81-91
ISSN
0166-2236 (ISSN-L)
DOI
10.1016/j.tins.2011.11.001
PMC
PMC3273608
OpenAlex
W2040114944
Cited by
200
References
126
Citations by year
2026: 12 · 2025: 13 · 2024: 9 · 2023: 5 · 2022: 21 · 2021: 16 · 2020: 15 · 2019: 13 · 2018: 15 · 2017: 12 · 2016: 10 · 2015: 14 · 2014: 20 · 2013: 12 · 2012: 13
FWCI
2.22
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Trends in Neurosciences (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute of Neurological Disorders and Stroke (R01NS076503)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD057580, R01HD038384)
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Keywords
Down syndrome, gene dosage, brain development, cortical development, cerebellar development, brain morphogenesis, mouse models of Down syndrome, mRNA levels
MeSH terms
Animals, Brain, Disease Models, Animal, Down Syndrome, Humans, Mice

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