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Uncovering the role of FOXA2 in the development of human serotonin neurons [RNA-seq]

ABSTRACT: Serotonin neurons (SNs) play a pivotal role in regulating brain development and function. Directed differentiation of SNs from human pluripotent stem cells (hPSCs) provides a useful tool for uncovering the mechanism of human SN development and the associated neuropsychiatric disorders. Previous studies reported that Foxa2 was expressed by serotonergic progenitors and functioned as a serotonergic fate determinant in mouse. However, the role of FOXA2 in human SNs development is unknown. Herein, we uncovered the role of FOXA2 through direct differentiation of FOXA2 lineage-tracing, FOXA2-knockout or inducible FOXA2-overexpression hPSCs into SNs. We found that SNs were not derived from FOXA2-lineage cells and FOXA2-knockout cells could still differentiate into mature and functional SNs, whereas FOXA2-overexpression enhanced the differentiation of floor plate (FP) cells rather than SNs. Coactivation of Sonic Hedgehog (SHH) and Retinoic acid (RA) signaling pathways promoted the differentiation towards SNs. In conclusion, FOXA2 is not intrinsically required for human SNs differentiation and simultaneous activation of SHH and RA signaling pathways could improve human SN differentiation by suppressing the differentiation towards FOXA2-positive FP cells. This study innovatively uncovers the role of FOXA2 in human SN development and provides a more efficient strategy to generate human SNs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE214605 | GEO | 2023/09/07

REPOSITORIES: GEO

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Critical role of FGF, RA, and WNT signaling for otic lineage specification from human PSCs in a 2D/3D-combined differentiation system

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