TP53 promotes lineage commitment of human embryonic stem cells through ciliogenesis and sonic hedgehog signaling
Sushama Sivakumar, Shu‐Tao Qi, Ningyan Cheng, Adwait Amod Sathe, Mohammed Kanchwala, Ashwani Kumar, Bret M. Evers, Chao Xing, Hongtao Yu
Abstract
hESCs exhibit increased proliferation rates, mitotic errors, and low-grade structural aneuploidy; produce poorly differentiated immature teratomas in mice; and fail to differentiate into neural progenitor cells (NPCs) in vitro. Genome-wide CRISPR screen reveals requirements of ciliogenesis and sonic hedgehog (Shh) pathways for hESC differentiation into NPCs. TP53 deletion causes abnormal ciliogenesis in neural rosettes. In addition to restraining cell proliferation through CDKN1A, TP53 activates the transcription of BBS9, which encodes a ciliogenesis regulator required for proper Shh signaling and NPC formation. This developmentally regulated transcriptional program of TP53 promotes ciliogenesis, restrains Shh signaling, and commits hESCs to neural lineages.