Altered patterning of trisomy 21 interneuron progenitors
Yathindar Giffin-Rao, Jie Sheng, Bennett Strand, Ke Xu, Leslie Huang, Margaret Medo, Kirstin A. Risgaard, Samuel Dantinne, Sruti Mohan, Aratrika Keshan, Roger A. Daley, Bradley Levesque, Lindsey Amundson, Rebecca Reese, André M. M. Sousa, Yunlong Tao, Daifeng Wang, Su‐Chun Zhang, Anita Bhattacharyya
Abstract
Individuals with Down syndrome (DS; Ts21), the most common genetic cause of intellectual disability, have smaller brains that reflect fewer neurons at pre- and post-natal stages, implicating impaired neurogenesis during development. Our stereological analysis of adult DS cortex indicates a reduction of calretinin-expressing interneurons. Using Ts21 human induced pluripotent stem cells (iPSCs) and isogenic controls, we find that Ts21 progenitors generate fewer COUP-TFII+ progenitors with reduced proliferation. Single-cell RNA sequencing of Ts21 progenitors confirms the altered specification of progenitor subpopulations and identifies reduced WNT signaling. Activation of WNT signaling partially restores the COUP-TFII+ progenitor population in Ts21, suggesting that altered WNT signaling contributes to the defective development of cortical interneurons in DS.