TP53 promotes lineage commitment of human embryonic stem cells through ciliogenesis and sonic hedgehog signaling

Aneuploidy, defective differentiation, and inactivation of the tumor suppressor TP53 all occur frequently during tumorigenesis. Here, we probe the potential links among these cancer traits by inactivating TP53 in human embryonic stem cells (hESCs). TP53-/- 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.

Automated summary

Aneuploidy, defective differentiation, and inactivation of TP53 are common during tumorigenesis. In this study, TP53 was inactivated in hESCs to explore the links between these cancer traits. TP53-/- hESCs showed increased proliferation rates, mitotic errors, and low-grade structural aneuploidy. They also produced poorly differentiated immature teratomas in mice and failed to differentiate into NPCs in vitro. Genome-wide CRISPR screen revealed the importance of ciliogenesis and Shh pathways in hESC differentiation into NPCs. TP53 deletion resulted in abnormal ciliogenesis in neural rosettes. TP53 transcriptionally activated BBS9, which is 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.