The Notch Intracellular Domain Has an RBPj-Independent Role during Mouse Hair Follicular Development

Abstract

Ligand-dependent activation, γ-secretase-processed cleavage, and RBPj-mediated downstream transcriptional activities of Notch receptors constitute the “canonical” Notch signaling pathway, which is essential for skin organogenesis. However, in Msx2-Cre mice, keratinocyte-specific deletion of the Rbpj gene in utero produced a significantly milder phenotype than either global Notch or γ-secretase loss. Herein, we investigated the underlying mechanisms for this apparent non-canonical signal using mouse genetics. We found no evidence that ligand back signaling contributed to skin organogenesis. The perdurance of RBPj protein did not establish an epigenetic memory of a canonical signal in the youngest epidermal stem cells, and Notch targets were not de-repressed. We provide evidence that γ-secretase-dependent but RBPj-independent NICD activity operating in the first hair follicles is responsible for a delay in follicular destruction, which results in lower serum TSLP levels, milder B-cell Lymphoproliferative Disease, and improved survival in Msx2-Cre+/tg;Rbpjf/f mice. Minimal amounts of NICD were sufficient for rescue, which was not mediated by transcription, suggesting that NICD is acting through a novel mechanism.

Notch signalling defines dorsal root ganglia neuroglial fate choice during early neural crest cell migration

“…While the exact nature of this phenomenon remains unclear, the differences between our data and that from Rbpj deletion may indicate other roles for Rbpj and/or Mib1 outside of the Notch pathway, or that some Notch activity remains in these models. Notably, Notch has been shown to signal independently of Rbpj in some circumstances [26], and Rbpj has Notch-independent transcriptional targets [27]. Mib1 also has roles outside of regulating Notch ligands [28–30], and it is likely that other ubiquitinated targets of Mib1 are yet to be identified, which may contribute to the phenotype observed.…”

The Varied Roles of Notch in Cancer

“…In addition to the canonical Notch signaling pathway shown in Figure 3, in some experimental systems it has been noted that deletion of RBPJ fails to precisely mimic the effects of pan-Notch receptor inhibition, for example through blockade with gamma-secretase inhibitors or deletion of multiple Notch genes (57). This has been taken as evidence of alternative non-canonical Notch signaling mechanisms; however, the details of how non-canonical signaling occurs and its contribution to pathophysiologic states such as cancer remains obscure.…”

Targeting the Notch Signaling Pathway in Chronic Inflammatory Diseases

“…There is also some evidence to support the existence of noncanonical Notch signaling [reviewed in (16,17)]. Type I noncanonical signaling involves Notch activation and transfer of activation signals independent of RBP-Jk (NICD-dependent but RBP-Jk-independent) (18,19); Type II involves activation of Notch target genes independent of proteolytic cleavage of Notch and RBP-Jk activation (NICD-and RBP-Jk-independent) (20); Type III involves RBP-Jk-dependent gene activation without receptor cleavage and NICD release (21,22). Several signaling pathways might be involved, such as Wnt, NfkB, HIF and PI3K/ AKT.…”