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

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.

Asynchronous excitatory neuron development in an isogenic cortical spheroid model of Down syndrome

“…To assess the influence of variability in individual genome on DEX gene discovery, we repeated the analyses replacing Olmos-Serrano et al, 2016 dataset with Palmer et al, 2021 (all) dataset ( Supplemental Figure 8A-D ). We first observed that Palmer et al, 2021 contained fewer unique HSA21 DEX genes (16 of 111, 14.4%) than Olmos-Serrano et al 2016 (17 of 45, 37.8%), when compared to our dataset and Klein et al, 2022 ( Supplemental Figure 8A ). As expected, most HSA21 DEX genes (95 of 98, 96.9%) from Palmer et al, 2021 (old fem.)…”

“…We first investigated the DEX genes from each study located on chromosome 21 (HSA21) and found statistically significant overlaps between every pair of datasets with p < 0.001 ( Figure 5A,B ). Particularly, 45 (88%) and 43 (84%) out of the 51 HSA21 DEX genes from our current dataset were also DEX in the Klein et al, 2022 and Palmer et al, 2021 (old fem.) datasets, respectively.…”

“…(C) Venn diagram showing overlap of DEX genes on HAS21 between all four datasets as in (A) and (B). (D) Venn diagram showing overlap of DEX genes on all chromosomes except HAS21 between the current, Klein et al, 2022 and Palmer et al, 2021 datasets. Circle size represents number of DEX genes.…”

“…Circle size represents number of DEX genes. (E) Venn diagram showing overlap of DEX genes on all chromosomes except HAS21 between the current, Klein et al, 2022 and Olmos-Serrano et al, 2016 datasets. Circle size represents number of DEX genes.…”

“…Only data of old female (old fem.) samples are included from Palmer et al, 2021 dataset and only data of day 8 WC-24-02-DS (D8) iPSC cultures are included from Klein et al, 2022. Size of the text in all panels represents number of DEX genes.…”