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.
Cell Rep. 2022 Feb 15;38(7):110395. doi: 10.1016/j.celrep.2022.110395.
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.
非整倍体、分化缺陷和肿瘤抑制因子 TP53 的失活在肿瘤发生过程中经常发生。在这里，我们通过在人胚胎干细胞（hESC）中失活 TP53 来探究这些癌症特征之间的潜在联系。TP53 hESC 表现出增殖率增加、有丝分裂错误和低度结构非整倍体；在小鼠中产生分化不良的不成熟畸胎瘤；并且不能在体外分化为神经祖细胞（NPC）。全基因组 CRISPR 筛选揭示了纤毛发生和 sonic hedgehog (Shh) 途径对于 hESC 分化为 NPC 的需求。TP53 缺失导致神经玫瑰花结中的异常纤毛发生。除了通过 CDKN1A 抑制细胞增殖外，TP53 还激活了 BBS9 的转录，BBS9 编码一种纤毛发生调节剂，对于正确的 Shh 信号传导和 NPC 形成是必需的。TP53 的这种发育调控转录程序促进纤毛发生、抑制 Shh 信号传导，并促使 hESC 向神经谱系分化。
