Khalili Saeed, Ballios Brian G, Belair-Hickey Justin, Donaldson Laura, Liu Jeff, Coles Brenda L K, Grisé Kenneth N, Baakdhah Tahani, Bader Gary D, Wallace Valerie A, Bernier Gilbert, Shoichet Molly S, van der Kooy Derek
Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
Department of Ophthalmology and Vision Sciences, University of Toronto, 340 College Street, Suite 400, Toronto, Ontario M5T 3A9, Canada.
Stem Cell Res. 2018 Dec;33:215-227. doi: 10.1016/j.scr.2018.11.005. Epub 2018 Nov 13.
During development, multipotent progenitors undergo temporally-restricted differentiation into post-mitotic retinal cells; however, the mechanisms of progenitor division that occurs during retinogenesis remain controversial. Using clonal analyses (lineage tracing and single cell cultures), we identify rod versus cone lineage-specific progenitors derived from both adult retinal stem cells and embryonic neural retinal precursors. Taurine and retinoic acid are shown to act in an instructive and lineage-restricted manner early in the progenitor lineage hierarchy to produce rod-restricted progenitors from stem cell progeny. We also identify an instructive, but lineage-independent, mechanism for the specification of cone-restricted progenitors through the suppression of multiple differentiation signaling pathways. These data indicate that exogenous signals play critical roles in directing lineage decisions and resulting in fate-restricted rod or cone photoreceptor progenitors in culture. Additional factors may be involved in governing photoreceptor fates in vivo.
在发育过程中，多能祖细胞经历时间受限的分化，成为有丝分裂后的视网膜细胞；然而，视网膜发生过程中祖细胞分裂的机制仍存在争议。通过克隆分析（谱系追踪和单细胞培养），我们鉴定出了源自成年视网膜干细胞和胚胎神经视网膜前体的视杆细胞与视锥细胞谱系特异性祖细胞。研究表明，牛磺酸和视黄酸在祖细胞谱系层次结构的早期以一种指导性的、谱系受限的方式发挥作用，从干细胞后代中产生视杆细胞受限的祖细胞。我们还确定了一种通过抑制多种分化信号通路来指定视锥细胞受限祖细胞的指导性但不依赖谱系的机制。这些数据表明，外源性信号在指导谱系决定以及在培养中产生命运受限的视杆或视锥光感受器祖细胞方面发挥着关键作用。体内控制光感受器命运可能还涉及其他因素。
