Regulation of ganglion cell production by notch signaling during retinal development

Abstract

Although progenitor cells in developing vertebrate retina are capable of producing all retinal cell types, they are competent to produce only certain cell types at a given time, and this competence changes as development progresses. We asked whether a change in progenitor cell competence is primarily responsible for ending production of a specific cell type, the retinal ganglion cell. Reducing Notch expression using an antisense oligonucleotide in vitro or in vivo increased ganglion cell genesis. The antisense treatment could reinitiate ganglion cell genesis after it had terminated in a region of the retina, but only for a brief period. The failure of the Notch antisense treatment to reinitiate ganglion cell production after this period was not due to the lack of receptor or ligand expression, as both Notch-1 and Delta-1 were still expressed. The failure of the Notch antisense treatment to reinitiate ganglion cell production is consistent with the suggestion that the intrinsic competence of progenitor cells changes as development progresses. Because reducing Notch signaling can reinitiate ganglion cell production for a brief period after ganglion cell production has normally ceased, it appears that ganglion cell production initially ends in a region of the retina because of cell-cell interactions and not because progenitor cells lose the competence to make ganglion cells. Notch signaling appears to temporarily prevent production of ganglion cells in a region, while some other signal must initiate a change in progenitor cell competence, thus permanently ending the possibility of further ganglion cell production.

Acheate‐scute like 1 (Ascl1) is required for normal delta‐like (Dll) gene expression and notch signaling during retinal development

“…Previous analyses of loss of Notch signaling during retinal development have consistently shown increased neural differentiation and inhibition of progenitors/gliogenesis (Dorsky et al, 1995;Austin et al, 1995;Tomita et al, 1996a;Henrique et al, 1997;Dorsky et al, 1997;Furukawa et al, 2000;Hojo et al, 2000;Satow et al, 2001;Silva et al, 2003;Takatsuka et al, 2004;Nelson et al, 2006;Jadhev et al, 2006;Yaron et al, 2006;Nelson et al, 2007a). Notch inactivation in early embryonic progenitors increases early retinal neurons (Nelson et al, 2007a), whereas Notch inactivation in later postnatal progenitors increases differentiation of late retinal cell types and decreases glial differentiation (Fig 8 A normal, Fig 8 B Notch inactivation in LP; Nelson et al, 2007a).…”

“…Notch signaling maintains the progenitor pool during the course of retinal development, and regulates the evolutionary conserved sequence of progenitor cell differentiation into the six types of neurons and one type of glia (Dorsky et al, 1995;Austin et al, 1995;Tomita et al, 1996a;Henrique et al, 1997;Dorsky et al, 1997;Furukawa et al, 2000;Hojo et al, 2000;Satow et al, 2001;Silva et al, 2003;Takatsuka et al, 2004;Nelson et al, 2006;Jadhev et al, 2006;Yaron et al, 2006;Nelson et al, 2007a). While most of these studies have demonstrated key functions of Notch and the downstream signaling components in progenitor cells, relatively little attention has been given to upstream components, such as the source of Delta ligands and their respective regulation.…”

Notch1 functions to suppress cone-photoreceptor fate specification in the developing mouse retina

“…Development 133 (7) Dorsky et al, 1997;Furukawa et al, 2000;Perron and Harris, 2000;Rapaport and Dorsky, 1998;Silva et al, 2003). In this case, it follows that premature loss of Notch1 activity in the RPCs of the peripheral retina during early embryogenesis (as in the Notch1 f/f ;␣-Cre mice) would result in the excessive differentiation of Notch1 -RPCs into cell types normally born during the corresponding early stages of retinogenesis: ganglion, cone, horizontal and amacrine cells (Fig.…”

“…Notch1 activity has been implicated in the inhibition of ganglion cell fate. This is based on the observation that ganglion cell production increases following antisense treatment of chick retinas with CNotch-1 or its ligand CDelta-1 (Ahmad et al, 1997;Austin et al, 1995;Silva et al, 2003). In contrast to these observations, analysis of the phenotype of Hes1 mutant embryos revealed premature differentiation of precursors into rod and horizontal cells (Tomita et al, 1996).…”

“…This was suggested, for example, following antisense treatment of chick retina, which resulted in an increased number of ganglion cells (Austin et al, Notch1 functions to suppress cone-photoreceptor fate specification in the developing mouse retina 1995; Waid and McLoon, 1998). Such an effect on cell fate due to Notch1 reduction is more pronounced at early stages and seems to be gradually lost during later stages of retinal development (Silva et al, 2003), indicating that differences in the intrinsic makeup of the progenitors determine their eventual response to Notch1 reduction. The most direct evidence for the role of Notch in cell-type specification in the retina was obtained from a study of mice deficient in one of the Notch1 effectors, Hes1.…”