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Stem Cells 2012 Dec 01;3012:2784-95. doi: 10.1002/stem.1231.
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Hes4 controls proliferative properties of neural stem cells during retinal ontogenesis.

El Yakoubi W , Borday C , Hamdache J , Parain K , Tran HT , Vleminckx K , Perron M , Locker M .

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.

PubMed ID: 22969013
PMC ID: PMC3549485
Article link: Stem Cells

Species referenced: Xenopus laevis
Genes referenced: calb1 ccnd1 ctrl hes4 nr3c1 pax2 pax6 ptch1 rpe shh

Article Images: [+] show captions
References [+] :
Agathocleous, A general role of hedgehog in the regulation of proliferation. 2007, Pubmed