RBL2-E2F-GCN5 guide cell fate decisions during tissue specification by regulating cell-cycle-dependent fluctuations of non-cell-autonomous signaling

Journal article

The retinoblastoma family proteins (RBs) and E2F transcription factors are cell-autonomous regulators of cell-cycle progression, but they also impact fate choice in addition to tumor suppression. The range of mechanisms involved remains to be uncovered. Here, we show that RBs, particularly RBL2/p130, repress WNT ligands such as WNT4 and WNT8A, thereby directing ectoderm specification between neural crest to neuroepithelium. RBL2 achieves this function through cell-cycle-dependent cooperation with E2Fs and GCN5 on the regulatory regions of WNT loci, which direct neuroepithelial versus neural crest specification by temporal fluctuations of WNT/β-catenin and DLL/NOTCH signaling activity. Thus, the RB-E2F bona fide cell-autonomous axis controls cell fate decisions, and RBL2 regulates field effects via WNT ligands. This reveals a non-cell-autonomous function of RBL2-E2F in stem cell and tissue progenitor differentiation that has broader implications for cell-cycle-dependent cell fate specification in organogenesis, adult stem cells, tissue homeostasis, and tumorigenesis.

Authors: Militi, S; Nibhani, R; Jalali, M; Pauklin, S

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Cell Press
• Journal: Cell Reports
• Volume: 42
• Issue: 9
• Article number: 113146
• Publication date: 2023-09-19
• Acceptance date: 2023-08-31
• DOI: 10.1016/j.celrep.2023.113146
• EISSN: 2211-1247
• ISSN: 2639-1856
• Pmid: 37725511
• Language: English
• Keywords: cell division; signal transduction; E2F transcription factors; retinoblastoma protein; FFR; body patterning; cell cycle; cell differentiation