Trisomy 21 Perturbs Oligodendrocyte Developmental States and Oligo-Neuron Communication in Human Forebrain…

Abstract

Intellectual disability is a hallmark of Down syndrome (DS), caused by the triplication of human chromosome 21. Abnormal neuronal connectivity and impaired myelination are consistently observed in DS, yet the underlying mechanisms remain poorly understood. Here, we used DS-derived isogenic induced pluripotent stem cell-derived forebrain assembloids (FAs) to investigate oligodendrocyte lineage cell (OLLC) development and neuron-glia interactions. Trisomic FAs exhibited an expansion of BCAS1+ pre-myelinating OLLCs, without a corresponding increase in myelin basic protein (MBP) expression. Transcriptomic analyses identified a euploid-enriched, trophic and maturation-supportive state (OLLC_2-TMS) and a trisomy-enriched synaptic interactions and differentiation state (OLLC_3-SID), lacking coordinated enrichment in myelination-promoting programs. Corresponding transcriptional signatures were identified in OLLCs from early postnatal human cortex. Increased excitatory neuronal contacts with pre-myelinating OLLCs accompanied ultrastructural myelin abnormalities in trisomic assembloids. Our findings suggest that trisomy redirects OLLC development toward a pre-myelinating state, uncoupling oligodendrocyte differentiation from productive myelination.

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BibTeX RIS

BibTeX

@misc{zeldich2026trisomy,
  title = {{Trisomy 21 Perturbs Oligodendrocyte Developmental States and Oligo-Neuron Communication in Human Forebrain Assembloids}},
  author = {E. Zeldich and N. B. Campbell and S. D. Khanna and M. J. Kim and E. K. Kharitonova and M. P. Weidman and C. Headings and N. X. Chai and C. Chung and S. M. Chung and G. Field and M. Linetsky and M. Thunemann and J. D. Campbell and M. D. Medalla},
  howpublished = {bioRxiv},
  year = {2026},
  month = oct,
  doi = {10.64898/2026.10.30.763166},
  url = {https://www.biorxiv.org/content/10.64898/2026.10.30.763166v1},
  note = {CC BY},
}

RIS

TY  - UNPB
TI  - Trisomy 21 Perturbs Oligodendrocyte Developmental States and Oligo-Neuron Communication in Human Forebrain Assembloids
AU  - E. Zeldich
AU  - N. B. Campbell
AU  - S. D. Khanna
AU  - M. J. Kim
AU  - E. K. Kharitonova
AU  - M. P. Weidman
AU  - C. Headings
AU  - N. X. Chai
AU  - C. Chung
AU  - S. M. Chung
AU  - G. Field
AU  - M. Linetsky
AU  - M. Thunemann
AU  - J. D. Campbell
AU  - M. D. Medalla
PY  - 2026
DA  - 2026/10/30
PB  - bioRxiv
DO  - 10.64898/2026.10.30.763166
UR  - https://www.biorxiv.org/content/10.64898/2026.10.30.763166v1
AB  - Intellectual disability is a hallmark of Down syndrome (DS), caused by the triplication of human chromosome 21. Abnormal neuronal connectivity and impaired myelination are consistently observed in DS, yet the underlying mechanisms remain poorly understood. Here, we used DS-derived isogenic induced pluripotent stem cell-derived forebrain assembloids (FAs) to investigate oligodendrocyte lineage cell (OLLC) development and neuron-glia interactions. Trisomic FAs exhibited an expansion of BCAS1+ pre-myelinating OLLCs, without a corresponding increase in myelin basic protein (MBP) expression. Transcriptomic analyses identified a euploid-enriched, trophic and maturation-supportive state (OLLC_2-TMS) and a trisomy-enriched synaptic interactions and differentiation state (OLLC_3-SID), lacking coordinated enrichment in myelination-promoting programs. Corresponding transcriptional signatures were identified in OLLCs from early postnatal human cortex. Increased excitatory neuronal contacts with pre-myelinating OLLCs accompanied ultrastructural myelin abnormalities in trisomic assembloids. Our findings suggest that trisomy redirects OLLC development toward a pre-myelinating state, uncoupling oligodendrocyte differentiation from productive myelination.
ER  -

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