Hes4 controls proliferative properties of neural stem cells during retinal ontogenesis

Stem Cells. 2012 Dec;30(12):2784-95. doi: 10.1002/stem.1231.


The retina of fish and amphibian contains genuine neural stem cells located at the most peripheral edge of the ciliary marginal zone (CMZ). However, their cell-of-origin as well as the mechanisms that sustain their maintenance during development are presently unknown. We identified Hes4 (previously named XHairy2), a gene encoding a bHLH-O transcriptional repressor, as a stem cell-specific marker of the Xenopus CMZ that is positively regulated by the canonical Wnt pathway and negatively by Hedgehog signaling. We found that during retinogenesis, Hes4 labels a small territory, located first at the pigmented epithelium (RPE)/neural retina (NR) border and later in the retinal margin, that likely gives rise to adult retinal stem cells. We next addressed whether Hes4 might impart this cell subpopulation with retinal stem cell features: inhibited RPE or NR differentiation programs, continuous proliferation, and slow cell cycle speed. We could indeed show that Hes4 overexpression cell autonomously prevents retinal precursor cells from commitment toward retinal fates and maintains them in a proliferative state. Besides, our data highlight for the first time that Hes4 may also constitute a crucial regulator of cell cycle kinetics. Hes4 gain of function indeed significantly slows down cell division, mainly through the lengthening of G1 phase. As a whole, we propose that Hes4 maintains particular stemness features in a cellular cohort dedicated to constitute the adult retinal stem cell pool, by keeping it in an undifferentiated and slowly proliferative state along embryonic retinogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Basic Helix-Loop-Helix Transcription Factors / biosynthesis*
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Cell Cycle / physiology
  • Cell Differentiation / physiology
  • Cell Growth Processes / physiology
  • Female
  • Gene Expression Regulation, Developmental
  • Hedgehog Proteins / metabolism
  • Immunohistochemistry
  • Male
  • Neural Stem Cells / cytology*
  • Neural Stem Cells / metabolism
  • Retina / cytology*
  • Retina / embryology*
  • Retina / metabolism
  • Retinal Pigment Epithelium / cytology
  • Retinal Pigment Epithelium / embryology
  • Retinal Pigment Epithelium / metabolism
  • Signal Transduction
  • Wnt Signaling Pathway
  • Xenopus Proteins / biosynthesis*
  • Xenopus Proteins / genetics
  • Xenopus laevis


  • Basic Helix-Loop-Helix Transcription Factors
  • HES4 protein, Xenopus
  • Hedgehog Proteins
  • Xenopus Proteins