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. Stem Cells 2012;30:2784–2795

SOX2OT knockdown derived changes in mitotic regulatory gene network of cancer cells

“…In vertebrate embryos, SOX2OT expression is dynamically regulated highly expressed in developing central nervous system [14]. Concordantly we found some central nervous system development and maintenance key regulators including: JAG1 [37], MDK [38], PKD2 [39], HES4 [40] and the eye formation regulator such as HIPK1 [41], de-regulated along with SOX2OT inhibition. These findings may suggest a mechanism for SOX2OT in CNS and eye development.…”

Spatial transcriptome analysis reveals Notch pathway-associated prognostic markers in IDH1 wild-type glioblastoma involving the subventricular zone

“…Little is known about the particular function of HES4 in stem cells and cancer. HES4 was shown to keep retinal precursor cells of the Xenopus ciliary margin zone in an undifferentiated and slowly proliferative state [36]. In human B cells, HES4 inhibits early differentiation and acts as a tumor suppressor with epigenetic silencing in B cell acute lymphoblastic leukemia [37].…”

Notch signaling differentially regulatesAtoh7andNeurog2in the distal mouse retina

“…This suggests that the boundary between zones 1 and 2 could be somewhat arbitrary, as it is based on gene expression differences. Nonetheless, previous subdivision of the adult frog ciliary marginal zone, via distinct patterns of gene expression, later led to identification of retinal stem cells (Perron et al, 1998;Perron and Harris, 2000;El Yakoubi et al, 2012). To understand mammalian retinal neurogenesis progression fully, new methods for following wave progression in real time and three dimensions will be needed.…”