# Molecular Mechanisms of Defective Oligodendrocyte Differentiation in Down Syndrome

> **NIH NIH F31** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2020 · $45,520

## Abstract

ABSTRACT
Down syndrome (DS) is caused by triplication of chromosome 21 (HSA21) and is the most common genetic
cause of intellectual disability with a prevalence of 1 in 750 live births. However exactly how the increase in
genetic material leads to the intellectual disability is unknown. Trisomy 21 has been shown to alter gene
expression patterns across the entire transcriptome in DS. One of these alterations is the downregulation of
network of genes regulating the oligodendrocyte (OL) lineage. This dysregulated gene expression identifies
perturbed OL production as the potential underlying cellular mechanism of the observed white matter deficit in
DS. Generation of oligodendrocyte precursor cells (OPCs) is dependent on the initiation of Olig2 by the
morphogen Sonic hedgehog (SHH). However, in DS both of these crucial components of OPC genesis are
impaired. Trisomic cells have a decreased mitogenic response to SHH. This decreased responsiveness to SHH
may alter the expression of one of its downstream gene targets, the transcription factor Olig2, whose expression
is crucial for OPC specification. Once activated, Olig2 induces the expression of a complex transcriptional
network that controls the differentiation and eventual maturation of OPCs into OL. In addition to the initial altered
SHH-mediated activation, the triplication and mis-expression of Olig2 in trisomic cells may compound the initial
transcriptional changes and further dysregulate downstream gene expression. This project aims to examine the
molecular consequences of these known perturbations in trisomic cells and how they lead to changes in OPC
development by differentiating isogenic pairs of euploid and trisomic induced pluripotent stem cell (iPSCs) lines
derived from people with DS into neural progenitor cells (NPCs) and OPCs. In Aim 1 we will test the effect
dysfunctional SHH signaling has on OPC generation in DS by increasing the activation of the SHH signaling
pathway both through application of a Smoothened agonist (SAG) and shRNA knockdown of the initial SHH
receptor PTCH which is overexpressed in DS. In Aim 2 we will focus on how triplication of Olig2 affects its
function as a key transcription factor regulating the transcriptional network by identifying differential binding of
the transcription factor between trisomic and euploid cells throughout OL development. As a direct test of the
effect transcription factor triplication has on OPC related transcriptional networks, we will perform RNA-seq at
different OPC developmental stages and use weighted gene co-expression analysis (WGCNA) to identify the
modules that contain the genes identified via ChIP-seq differential binding and examine how these networks as
a whole differ between euploid and trisomic cells. Together these aims will elucidate, for the first time, the
molecular underpinnings of alterations in oligodendrocyte development that may be leading to the
observed white matter deficit in DS.

## Key facts

- **NIH application ID:** 10145425
- **Project number:** 1F31NS118968-01A1
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Jenny Adele Klein
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 1
- **Project period:** 2020-09-28 → 2022-08-27

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10145425

## Citation

> US National Institutes of Health, RePORTER application 10145425, Molecular Mechanisms of Defective Oligodendrocyte Differentiation in Down Syndrome (1F31NS118968-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10145425. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*