# Investigating Trisomy 21 Impact on Human Neural Cell Development and Function Using "Trisomy Silencing" in vitro

> **NIH NIH F31** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2022 · $33,958

## Abstract

PROJECT SUMMARY
Down syndrome (DS), trisomy 21, is the most common intellectual disorder affecting millions and also is a form
of early-onset Alzheimer Disease (AD). Understanding of DS pathology has been hindered by the complexity
caused by overexpression of the ~250 genes on chromosome 21 (chr21). Many reports describe a diverse range
of developmental and functional pathologies in the DS brain. However, there is conflicting evidence even as to
which brain regions or cell types are impacted. Furthermore, few studies address when pathology arises and
when it remains reversible. Therefore, better understanding of the exact impact of DS on brain development and
function, when said effects occur, and identification of mechanistic causes in specific brain cell types is critical.
Reports from mouse models, human induced pluripotent stem cells (iPSCs), and post-mortem DS brain samples
regarding the impact of DS on brain development and function are conflicted. Furthermore, when during
development the impacts of DS occur and which chr21 genes are responsible are unknown. Preliminary results
show that the clonal variability between isogenic disomic and trisomic cell lines was too great to establish any
neurodevelopmental effect of trisomy even when organoids variability was well controlled. Surprisingly, AD-
related Aβ pathology was still observed. To circumvent variability between cell lines our strategy will be to
manipulate over-expression of chr21 in several trisomic cell lines. By inserting an inducible XIST transgene into
the extra chr21, our lab has demonstrated comprehensive chromosomal silencing using endogenous machinery
for dosage compensation. Our XIST-inducible system for “trisomy silencing” reduces variability by allowing the
study of nearly identical cells, with or without extra chr21 expression. Using this system, the Lawrence lab has
demonstrated that DS potentially delays neurogenesis by prolonging neural progenitor cell (NPC) fate during
neuronal monolayer differentiation. Prolonged NPC cycling is known to alter cell fate and therefore we will
examine later stages of neurodevelopment that may alter brain cell-type composition. At the same time, we will
examine if trisomy silencing can correct an established AD-related cell pathology in DS organoids.
We will also use these approaches to examine the impact of trisomy 21 on global transcription in specific cell
types relating to cell pathologies. A current theme in DS research is that trisomy 21 causes very broad changes
in expression of non-chr21 genes. Through transcriptomics many studies have reported that genome-wide
impacts may alter specific genes/pathways, impacting both the development and activity of different neural cell
types. However, work in our lab suggests other differences between samples, not due to trisomy, may account
for much of this “global perturbation”. The hypothesis for this proposal is that trisomy 21 alters the relative
proportions of neural cell types in the br...

## Key facts

- **NIH application ID:** 10543409
- **Project number:** 5F31HD106741-02
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Eric Christopher Larsen
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $33,958
- **Award type:** 5
- **Project period:** 2021-08-19 → 2025-08-18

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10543409

## Citation

> US National Institutes of Health, RePORTER application 10543409, Investigating Trisomy 21 Impact on Human Neural Cell Development and Function Using "Trisomy Silencing" in vitro (5F31HD106741-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10543409. Licensed CC0.

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