title: Hes4 controls proliferative properties of neural stem cells during retinal ontogenesis.
abstract: 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.
authors.affiliation: UPR CNRS 3294, University Paris-Sud, Orsay, France.
authors.forename: Warif
authors.initials: W
authors.lastname: El Yakoubi
authors.forename: Caroline
authors.initials: C
authors.lastname: Borday
authors.forename: Johanna
authors.initials: J
authors.lastname: Hamdache
authors.forename: Karine
authors.initials: K
authors.lastname: Parain
authors.forename: Hong Thi
authors.initials: HT
authors.lastname: Tran
authors.forename: Kris
authors.initials: K
authors.lastname: Vleminckx
authors.forename: Muriel
authors.initials: M
authors.lastname: Perron
authors.forename: Morgane
authors.initials: M
authors.lastname: Locker
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis* / Q000235:genetics; D002453:Cell Cycle / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D005260:Female; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D058953:Neural Stem Cells / Q000166:cytology* / Q000378:metabolism; D012160:Retina / Q000166:cytology* / Q000196:embryology* / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D015398:Signal Transduction; D060449:Wnt Signaling Pathway; D029867:Xenopus Proteins / Q000096:biosynthesis* / Q000235:genetics; D014982:Xenopus laevis
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D053823:Hedgehog Proteins; D029867:Xenopus Proteins; C439928:HES4 protein, Xenopus