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

Stefania Militi1, Reshma Nibhani1, Morteza Jalali2

  • 1Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Old Road, Headington, Oxford OX3 7LD, UK.

Cell Reports
|September 19, 2023
PubMed

Insights

Retinoblastoma proteins (RBs) and E2F factors regulate cell fate. RBL2/p130 represses WNT ligands, directing ectoderm specification and revealing non-cell-autonomous roles in stem cell differentiation.

Area of Science:

  • Developmental Biology
  • Cell Biology
  • Molecular Biology

Background:

  • Retinoblastoma (RB) proteins and E2F transcription factors are key regulators of cell-cycle progression.
  • While known for tumor suppression, their role in cell fate decisions is less understood.
  • The precise mechanisms by which RBs influence cell fate remain to be fully elucidated.

Purpose of the Study:

  • To investigate the role of RB proteins, specifically RBL2/p130, in directing ectoderm specification.
  • To uncover the molecular mechanisms by which RBs control cell fate decisions.
  • To explore the non-cell-autonomous functions of the RB-E2F axis in stem cell differentiation.

Main Methods:

  • Analysis of RB protein interactions with E2F transcription factors and GCN5.
  • Investigation of RBL2/p130's regulation of WNT ligand expression (WNT4, WNT8A).
  • Assessment of WNT/β-catenin and DLL/NOTCH signaling pathway activity during ectoderm specification.

Main Results:

  • RBL2/p130 was found to repress WNT ligands (WNT4, WNT8A), influencing ectoderm fate.
  • RBL2/p130 cooperates with E2Fs and GCN5 in a cell-cycle-dependent manner on WNT gene regulatory regions.
  • This regulation directs neuroepithelial versus neural crest specification through temporal signaling fluctuations.

Conclusions:

  • The RB-E2F axis is a critical regulator of cell fate decisions, extending beyond cell-autonomous functions.
  • RBL2/p130 exhibits non-cell-autonomous control over stem cell and progenitor differentiation via WNT ligands.
  • These findings have significant implications for understanding organogenesis, tissue homeostasis, and tumorigenesis.
Keywords:
CP: Developmental biologyCP: Stem cell researchE2F transcription factorsWNT pathwayhuman induced pluripotent stem cellshuman pluripotent stem cellsneuroectoderm differentiationretinoblastoma family proteins

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