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

Abstract

Notch receptor-mediated cell-cell signaling is known to negatively regulate neurogenesis in both vertebrate and invertebrate species, while being implicated in promoting the acquisition of glial fates. We studied Notch1 function directly during retinal neurogenesis by selective Cre/loxP-triggered Notch1 gene inactivation in peripheral retinal progenitor cells (RPCs) prior to the onset of cell differentiation. Consistent with its previously established role, Notch1 inactivation led to dramatic alteration in the expression profile of multiple basic helix-loop-helix transcription factors, consequently prompting premature cell-cycle exit and neuronal specification. Surprisingly, however, Notch1 inactivation led to a striking change in retinal cell composition, with cone-photoreceptor precursors expanding at the expense of other early- as well as late-born cell fates. Intriguingly, the Notch1-deficient precursors adhered to the normal chronological sequence of the cone-photoreceptor differentiation program. Together, these findings reveal an unexpected role of Notch signaling in directly controlling neuronal cell-type composition, and suggest a model by which, during normal retinogenesis, Notch1 functions to suppress cone-photoreceptor fate, allowing for the specification of the diversity of retinal cell types.

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.…”

“…It is interesting to note that hyperproliferation was not observed in the early NIC-expressing retinae. This implies that although proper Notch1 function is necessary for normal retinal size (8,9) excess Notch activation is not sufficient to drive proliferation in the early retina, in keeping with observations of NIC introduction into early chick and Xenopus retinae (12,15). In addition, it implies that the progenitor progression does not result from a precise regulation of neuron production, e.g., a counting of the number or types of neurons produced.…”

“…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.…”

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.…”

Notch2 regulates BMP signaling and epithelial morphogenesis in the ciliary body of the mouse eye

“…Although Notch1 and Notch2 are expressed in the developing vertebrate eye (28,29), only Notch1 has been shown to prevent premature differentiation of retinal progenitors and control retinal progenitor proliferation and retinal lineage specification in the developing retina (30,31). In this study, we use a retinal pigmented epithelium (RPE)-specific Cre line, tyrosinase related protein 1 (Trp1)-Cre, to conditionally inactivate the function of Notch2 and show that it is required in the OCE to control CB morphogenesis.…”