Notch activity permits retinal cells to progress through multiple progenitor states and acquire a stem cell property

Abstract

Signaling through the Notch pathway regulates multiple aspects of development. The vertebrate retina allows an investigation of the basis for these various effects, because the major cell types of the retina arise from a common progenitor that expresses Notch1 . The Notch pathway was constitutively activated in distinct populations of retinal cells during development. Prolonged Notch activity in progenitor cells maintained cells in the progenitor state without perturbing temporal identity, promoting early progenitor characteristics early in development and late progenitor characteristics later in development. Eventually, constitutive Notch activation led these cells to acquire characteristics of glial and stem cells. In contrast, reactivating the Notch pathway in newly postmitotic retinal cells promoted mature glial cell formation in a subset of cells. These data suggest that prolonged Notch activity does not disrupt the normal progression of progenitor temporal states, and that down-regulating or overcoming Notch activity is required for proper formation of both neuronal and glial cell fates.

Generation of a ciliary margin-like stem cell niche from self-organizing human retinal tissue

“…5a). We manually dissected nonpigmented Rx::Venus-strong tissues in the tapered NR margin (CM-like tissues, hereafter) from hESCderived retina (day 60-85), dissociated them, and then subjected them to retinosphere culture (1,000 cells per well) 17,52,53 . For comparison, we dissected nonmarginal NR (central NR) tissues from the same aggregates.…”

Meis1 coordinates a network of genes implicated in eye development and microphthalmia

“…Nevertheless, whether direct or not, the poor Notch pathway activation, in conjunction with decreased expression of Ccnd1 and other microphthalmia-associated genes, could explain the Meis1 −/− microphthalmic phenotype. Indeed, Notch signaling controls the number of progenitors entering retinal differentiation: loss of Notch function forestalls retinal neurogenesis (Jadhav et al, 2006), whereas abnormal Notch receptor activation transiently increases retinal proliferation and differentiation (Esteve et al, 2011). Notably, Meis1 action on the Notch pathway and on microphthalmia-related genes could be linked since Sox1, Sox2 and Notch signaling have been shown to regulate each other's activity in various contexts (Genethliou et al, 2009;Kan et al, 2004;Neves et al, 2011).…”

In vitro and in vivo differentiation of human embryonic stem cells into retina‐like organs and comparison with that from mouse pluripotent epiblast stem cells

“…As for the induction of ocular tissues, lens and several retinal cell types were reported to have been differentiated from ES cells (Gong et al, 2008;Lamba et al, 2006;Osakada et al, 2008). Factors regulating the differentiation of the retinal tissues, such as Wnt2b, Wnt3a, Notch, Hes1, and RA (Jadhav et al, 2006;Kubo et al, 2003;Luo et al, 2006;Osakada et al, 2007;Tomita et al, 1996), were sequentially added to induce specific retinal cell lineages such as photoreceptor cells (Osakada et al, 2008). Co-cultures of ES cells and stromal cell lines (Aoki et al, 2008a,b;Hirano et al, 2003;Kawasaki et al, 2002;Ooto et al, 2003;Ueno et al, 2006) or developing chick retina (Ikeda et al, 2005;Sugie et al, 2005) were reported to successfully form differentiated photoreceptor cells, amacrine cells, horizontal cells, retinal ganglion cells, lens cells, and retinal pigmented epithelium from ES cells.…”