Multiple Roles of Notch Signaling in the Regulation of Epidermal Development

Abstract

Recent studies have shown that Notch signaling plays an important role in epidermal development, but the underlying molecular mechanisms remain unclear. Here, by integrating loss- and gain-of-function studies of Notch receptors and Hes1, we describe molecular information about the role of Notch signaling in epidermal development. We show that Notch signaling determines spinous cell fate and induces terminal differentiation by a mechanism independent of Hes1, but Hes1 is required for maintenance of the immature state of spinous cells. Notch signaling induces Ascl2 expression to promote terminal differentiation, while simultaneously repressing Ascl2 through Hes1 to inhibit premature terminal differentiation. Despite the critical role of Hes1 in epidermal development, Hes1 null epidermis transplanted to adult mice showed no obvious defects, suggesting that this role of Hes1 may be restricted to developmental stages. Overall, we conclude that Notch signaling orchestrates the balance between differentiation and immature programs in suprabasal cells during epidermal development.

Notch signaling represses p63 expression in the developing surface ectoderm

“…Notch signaling has been shown to be important for the commitment of basal keratinocytes to terminal differentiation during development Moriyama et al, 2008;Nguyen et al, 2006;Pan et al, 2004). Although several groups have deleted Notch signaling components and analyzed keratinocyte defects, alterations in epidermal specification have not been noted to date.…”

“…NICD translocates to the nucleus, where it interacts with the DNAbinding protein CSL/RBP-Jk and the coactivator Mastermind to promote the transcription of Notch target genes (Kopan and Ilagan, 2009). In the skin, canonical Notch signaling is required for the commitment of basal keratinocytes to terminal differentiation during development Moriyama et al, 2008;Nguyen et al, 2006;Pan et al, 2004). However, whether Notch signaling regulates epidermal keratinocyte specification directly is not known.…”

Notch1 maintains dormancy of olfactory horizontal basal cells, a reserve neural stem cell

“…For example, in keratinocytes, Notch1 blocks p63 expression and promotes differentiation. Conversely, p63 antagonizes Notch1 and prevents differentiation (31,34,52,53). Similarly, in mammary epithelial cells, Notch signaling reduces levels of ΔNp63 and mimics ΔNp63 depletion (35).…”

Development and Homeostasis of the Skin Epidermis

“…Monitoring the activation of the Notch pathway using an antibody against the active form of Notch, lineage-tracing experiments using Cre recombinase triggered by the activation of Notch1, or expression of Notch target gene Hes1 revealed that the Notch pathway is active mainly in suprabasal cells Vooijs et al 2007;Moriyama et al 2008). Complete inactivation of the Notch pathway in mice deficient for g-secretase 1 and 2 or multiple Notch receptors (Pan et al 2004) or the transcription factor that relays Notch signaling (RBP-Jk) or Hes1 (Moriyama et al 2008) leads to a lack of spinous differentiation and loss of skin barrier formation. Conversely, overexpression of Notch intracellular domain in the epidermis leads to spinous layer expansion (Uyttendaele et al 2004;.…”