Notch 1 inhibits photoreceptor production in the developing mammalian retina

Abstract

The transmembrane receptor Notch1 plays a role in development and homeostasis in vertebrates and invertebrates. The mammalian retina is an excellent tissue in which to dissect the precise role of Notch signaling in regulating cell fate and proliferation. However, a systematic analysis has been limited by the early embryonic lethality of Notch1-null mice. Here, Notch1 was conditionally removed from the murine retina either early or late in development. Removal of Notch1 early led to a reduction in the size of the retina as well as aberrant morphology. A decrease in the number of progenitor cells and premature neurogenesis accounted for the reduction in size. Unexpectedly, ablation of Notch1 in early progenitor cells led to enhanced cone photoreceptor production, and ablation of Notch1 at later points led to an almost exclusive production of rod photoreceptor cells. These data suggest that Notch1 not only maintains the progenitor state, but is required to inhibit the photoreceptor fate. These cone enriched mutant mice should prove to be a valuable resource for the study of this relatively rare mammalian photoreceptor cell type.

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

“…In contrast, activation of the Notch pathway in newly postmitotic cells led to a subset of cells with glial gene expression and proper glial morphology, in the absence of progenitor or stem cell characteristics, suggesting that proper glial differentiation requires a release from Notch activation. These data, together with recent findings that Notch can inhibit the formation of photoreceptor cells (8,9), support an iterative role for Notch in nervous system development. We propose that Notch signaling regulates the neuronal vs. glial fate choice, perhaps in the mitotic cell which is also using Notch signal to regulate the decision to produce a postmitotic daughter.…”

“…More recent studies have suggested an additional role for activated Notch in specifying or promoting a particular cell fate, the glial cell fate (4)(5)(6). Furthermore, Notch activity also has been shown to induce stem cell features and participate in neuronal subtype specification (7)(8)(9). These studies raise the question of how Notch activity can influence the generation of multiple cell fates, while also acting in a more generic fashion to preserve a progenitor pool.…”

SOX2 is a dose-dependent regulator of retinal neural progenitor competence

“…We present three independent sets of experiments demonstrating that Notch1 transcription is regulated by SOX2; an unbiased ChIP screen identified Notch1 as a direct target of SOX2 in vivo, DNase footprinting and Luciferase reporter assays showed that SOX2 can bind to Notch1 regulatory regions and regulate the levels of NOTCH1 expression in vitro, and finally, both NOTCH1 and its target Hes-5 are dramatically down-regulated in the retinas of Sox2 hypomorphic mice. Furthermore, ablation of NOTCH1 gives a retinal phenotype similar to that which we describe for Sox2-null mice (i.e., loss of RPCs) (Austin et al 1995;Waid and McLoon 1995;Ahmad et al 1997;Henrique et al 1997;Jadhav et al 2006), and the retinal phenotypes of both Hes-1 and Hes-5 mutant mice are strikingly similar to the phenotype observed in Sox2-hypomorphic mice, in that RPCs aberrantly differentiate and abnormal "rosette-like" structures are present (Ishibashi et al 1994;Tomita et al 1996). The lack of balance between lateral inhibitory signaling by NOTCH1 and proneural gene products results in differentiation of RPCs-a mechanism that may extend to other CNS progenitors.…”

Signaling and epigenetic regulation of pituitary development

“…It is hypothesized that the long duration or high intensity of Notch activity imposes irreversible changes in gene expression and/or epigenetic status and thus enables progenitor cells competent to adopt an alternative cell fate [22]. This is consistent with recent findings of Notch function in other developmental contexts [25][26][27][28]. Interestingly, it has been shown recently that the conserved first intron region of the Prop1 gene is capable of conferring dorsal expression of a transgene driven by a heterologous promoter, suggesting that this element is critical for the spatial expression of endogenous Prop1 during pituitary development.…”