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

doi:10.1016/j.celrep.2022.110395

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

Cell Rep. 2022 Feb 15;38(7):110395. doi: 10.1016/j.celrep.2022.110395.

Authors

Sushama Sivakumar¹, Shutao Qi², Ningyan Cheng¹, Adwait A Sathe³, Mohammed Kanchwala³, Ashwani Kumar³, Bret M Evers⁴, Chao Xing⁵, Hongtao Yu⁶

Affiliations

¹ Department of Pharmacology, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX 75390, USA.
² Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China; School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China.
³ Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
⁴ Department of Pathology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
⁵ Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
⁶ Department of Pharmacology, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX 75390, USA; Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China; School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China. Electronic address: yuhongtao@westlake.edu.cn.

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.

Keywords: BBS9; aneuploidy; neuronal differentiation; p53; primary cilia; sonic hedgehog; stem cell; transcription; tumor suppressor.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Motifs
Animals
CRISPR-Cas Systems / genetics
Cell Differentiation
Cell Line
Cell Lineage*
Cilia / metabolism*
Cytoskeletal Proteins / genetics
Cytoskeletal Proteins / metabolism
Genome, Human
Hedgehog Proteins / metabolism*
Human Embryonic Stem Cells / cytology*
Human Embryonic Stem Cells / metabolism*
Humans
Mice
Mice, Inbred NOD
Mice, SCID
Neural Stem Cells / metabolism
Neurogenesis / genetics
Organogenesis*
Signal Transduction*
Teratoma / pathology
Tumor Suppressor Protein p53 / chemistry
Tumor Suppressor Protein p53 / metabolism*

Substances

BBS9 protein, human
Cytoskeletal Proteins
Hedgehog Proteins
SHH protein, human
Tumor Suppressor Protein p53

Grants and funding

R01 GM124096/GM/NIGMS NIH HHS/United States