PT  - JOURNAL ARTICLE
AU  - Yathinder Giffin-Rao
AU  - Bennett Strand
AU  - Margaret Medo
AU  - Aratrika Keshan
AU  - Roger A. Daley, Jr.
AU  - Sruti Mohan
AU  - Samuel Dantienne
AU  - Bradley Levesque
AU  - Lindsey Amundson
AU  - Leslie Huang
AU  - Rebecca Reese
AU  - Daifeng Wang
AU  - Su-Chun Zhang
AU  - Anita Bhattacharyya
TI  - Altered patterning of interneuron progenitors in Down syndrome
AID  - 10.1101/2020.02.18.951756
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.02.18.951756
4099  - http://biorxiv.org/content/early/2020/02/19/2020.02.18.951756.short
4100  - http://biorxiv.org/content/early/2020/02/19/2020.02.18.951756.full
AB  - Multiple developmental processes go awry in Down syndrome (DS, trisomy 21, Ts21), the most common genetic cause of intellectual disability and a complex multigene disorder. DS individuals have smaller brains with reduced volume of frontal and temporal lobes, including hippocampus. This smaller brain volume corresponds to fewer neurons in the DS cortex measured at pre-and post-natal stages, implicating impaired neurogenesis during development. We employ Ts21 human induced pluripotent stem cells (iPSCs) and isogenic controls to identify disrupted interneuron developmental processes in DS. Interneuron progenitor specification, proliferation and migration is largely controlled by integrating known morphogen gradients, sonic hedgehog (SHH) and Wingless (WNT), and we find that Ts21 progenitors have altered patterning and generate different progenitor populations. Specifically, we find expression of WNT signaling genes is reduced and expression of GLI genes that regulate WNT and SHH signaling in this population is increased in Ts21 interneuron progenitors, suggesting Ts21 progenitors are patterned more ventrally and less caudally. Altered patterning affects lineage decisions and, in fact, fewer caudal interneuron progenitors expressing the transcription factor COUP-TFII differentiate from Ts21 iPSCs. In mouse, COUP-TFII+ progenitors are found in more caudal regions of the neurogenic regions, thus linking the patterning changes to altered generation of interneuron subpopulations. These data identify affected progenitor subpopulations in Ts21 and suggest that abnormal patterning of human Ts21 interneuron progenitors alters the generation of interneurons in DS and contributes to the reduced neurogenesis in DS.