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

Sushama Sivakumar, Shutao Qi, Ningyan Cheng, Adwait A. Sathe, Mohammed Kanchwala, Ashwani Kumar, Bret M. Evers, Chao Xing, Hongtao Yu

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number110395
JournalCell Reports
Volume38
Issue number7
DOIs
StatePublished - Feb 15 2022

Keywords

  • BBS9
  • aneuploidy
  • neuronal differentiation
  • p53
  • primary cilia
  • sonic hedgehog
  • stem cell
  • transcription
  • tumor suppressor

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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