Biphasic cell cycle defect causes impaired neurogenesis in down syndrome

Abstract

Impaired neurogenesis in Down syndrome (DS) is characterized by reduced neurons, increased glial cells, and delayed cortical lamination. However, the underlying cause for impaired neurogenesis in DS is not clear. Using both human and mouse iPSCs, we demonstrate that DS impaired neurogenesis is due to biphasic cell cycle dysregulation during the generation of neural progenitors from iPSCs named the “neurogenic stage” of neurogenesis. Upon neural induction, DS cells showed reduced proliferation during the early phase followed by increased proliferation in the late phase of the neurogenic stage compared to control cells. While reduced proliferation in the early phase causes reduced neural progenitor pool, increased proliferation in the late phase leads to delayed post mitotic neuron generation in DS. RNAseq analysis of late-phase DS progenitor cells revealed upregulation of S phase-promoting regulators, Notch, Wnt, Interferon pathways, and REST, and downregulation of several genes of the BAF chromatin remodeling complex. NFIB and POU3F4, neurogenic genes activated by the interaction of PAX6 and the BAF complex, were downregulated in DS cells. ChIPseq analysis of late-phase neural progenitors revealed aberrant PAX6 binding with reduced promoter occupancy in DS cells. Together, these data indicate that impaired neurogenesis in DS is due to biphasic cell cycle dysregulation during the neurogenic stage of neurogenesis.

Transcriptional consequences of trisomy 21 on neural induction

“…Canonical WNT signaling promotes stem cell proliferation and inhibition of progenitor apoptosis ( Dravid et al, 2005 ; Davidson et al, 2007 ; Lee et al, 2015 ). The decrease in canonical WNT signaling in our results correlates with decreased cell proliferation in T21 ( Sobol et al, 2019 ; Sharma et al, 2022 ). Overall, given the critical role of the canonical WNT signaling pathway in maintaining stemness and proliferation, these data may indicate that T21 cells are less responsive to cues to maintain or expand progenitor pools in the brain.…”

Extracellular Vesicle Treatment Alleviates Neurodevelopmental and Neurodegenerative Pathology in Cortical Spheroid Model of Down Syndrome

“…This was also confirmed in the Ts65Dn mouse model [ 30 ] and DS-derived organoid models [ 33 , 35 ]. However, other studies found increased numbers of neural progenitors in the SVZ region in the medial ganglionic eminence in Ts65Dn and Ts1Cje mouse models, leading to the enhanced generation of inhibitory neurons accompanied by a paucity in the number of excitatory neurons [ 84 , 85 ]. In addition, impaired neurogenesis was attributed to a biphasic cell cycle defect manifested in the diminished proliferating capacity of NPCs in the early stages, followed by increased proliferation affecting the neurogenic phase of the neurogenesis, as was shown in a DS-derived iPSC-based model [ 84 ].…”