Notch signaling represses p63 expression in the developing surface ectoderm

Tadeu, Ana; Horsley, Valerie

doi:10.1242/dev.093948

Cited by 64 publications

(76 citation statements)

References 59 publications

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“…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).…”

Section: Discussionmentioning

confidence: 99%

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

Herrick

Lin

Peterson

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The remarkable capacity of the adult olfactory epithelium (OE) to regenerate fully both neurosensory and nonneuronal cell types after severe epithelial injury depends on life-long persistence of two stem cell populations: the horizontal basal cells (HBCs), which are quiescent and held in reserve, and mitotically active globose basal cells. It has recently been demonstrated that down-regulation of the ΔN form of the transcription factor p63 is both necessary and sufficient to release HBCs from dormancy. However, the mechanisms by which p63 is down-regulated after acute OE injury remain unknown. To identify the cellular source of potential signaling mechanisms, we assessed HBC activation after neuron-only and sustentacular cell death. We found that ablation of sustentacular cells is sufficient for HBC activation to multipotency. By expression analysis, nextgeneration sequencing, and immunohistochemical examination, down-regulation of Notch pathway signaling is coincident with HBC activation. Therefore, using HBC-specific conditional knockout of Notch receptors and overexpression of N1ICD, we show that Notch signaling maintains p63 levels and HBC dormancy, in contrast to its suppression of p63 expression in other tissues. Additionally, Notch1, but not Notch2, is required to maintain HBC dormancy after selective neuronal degeneration. Taken together, our data indicate that the activation of HBCs observed after tissue injury or sustentacular cell ablation is caused by the reduction/elimination of Notch signaling on HBCs; elimination of Jagged1 expressed by sustentacular cells may be the ligand responsible.Notch | olfactory epithelium | reserve stem cell | trp63

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Section: Discussionmentioning

confidence: 99%

“…In NIH 3T3 cells, knockout of p63 inhibits Notchmediated transcription of Jagged1 (33). In the other direction, p63 can feedback to activate Notch pathway gene expression in some tissues (34)(35)(36). Thus, the relationship between Notch and p63 tends to be antagonistic, but is not absolutely so.…”

mentioning

confidence: 99%

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

Herrick

Lin

Peterson

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Reciprocal antagonistic interactions between DNp63 and Notch regulate epithelial cell fates (69)(70)(71). In the basal layer of epidermis, opposing gradients of p63 and Notch activation govern the balance between self-renewing and transit-amplifying cells (69).…”

Section: Notch Pathwaymentioning

confidence: 99%

Maintaining epithelial stemness with p63

et al. 2015

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In stratified epithelial and glandular tissues, homeostasis relies on the self-renewing capacity of stem cells, which are within the basal layer. The p53 family member p63 is an indispensable transcription factor for epithelial morphogenesis and stemness. A splice variant of the transcription factor p63 that lacks an amino-terminal domain, ΔNp63, is selectively found in the basal compartments of several ectoderm-derived tissues such as stratified and glandular epithelia, in which it is required for the replenishment of stem cells. Thus far, the transcriptional programs downstream of p63 in stemness regulation remain incompletely defined. Unveiling the molecular basis of stem cell self-renewal may be relevant in understanding how this process may contribute to cancer development. In this review, we specifically highlight experimental investigations, which suggest that p63 is a marker of normal epithelial stem cells and describe p63 transcriptional targets that may be involved in stemness regulation. Finally, we discuss relevant findings implicating p63 in epithelial cancer stem cell biology.

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“…S2). This distribution suggested that a dominant role for Notch1 in skin development (Demehri et al, 2008;Pan et al, 2004) and homeostasis (Demehri et al, 2009) reflected its function in the basal cell population (Tadeu and Horsley, 2013). To test whether N1ICD composition has any unique function in the skin, we examined the levels of the cytokine TSLP and performed a complete blood count (CBC) in the serum of animals with various combinations of Notch1 and Notch2 alleles (Fig.…”

Section: Outbred N12 and N21 Homozygous Mice Display No Overt Phenotypementioning

confidence: 99%

The intracellular domains of Notch1 and 2 are functionally equivalent during development and carcinogenesis

et al. 2015

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Although Notch1 and Notch2 are closely related paralogs and function through the same canonical signaling pathway, they contribute to different outcomes in some cell and disease contexts. To understand the basis for these differences, we examined in detail mice in which the Notch intracellular domains (N1ICD and N2ICD) were swapped. Our data indicate that strength (defined here as the ultimate number of intracellular domain molecules reaching the nucleus, integrating ligand-mediated release and nuclear translocation) and duration (half-life of NICD-RBPjk-MAML-DNA complexes, integrating cooperativity and stability dependent on shared sequence elements) are the factors that underlie many of the differences between Notch1 and Notch2 in all the contexts we examined, including T-cell development, skin differentiation and carcinogenesis, the inner ear, the lung and the retina. We were able to show that phenotypes in the heart, endothelium, and marginal zone B cells are attributed to haploinsufficiency but not to intracellular domain composition. Tissue-specific differences in NICD stability were most likely caused by alternative scissile bond choices by tissue-specific γ-secretase complexes following the intracellular domain swap. Reinterpretation of clinical findings based on our analyses suggests that differences in outcome segregating with Notch1 or Notch2 are likely to reflect outcomes dependent on the overall strength of Notch signals.

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Notch signaling represses p63 expression in the developing surface ectoderm

Cited by 64 publications

References 59 publications

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

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

Maintaining epithelial stemness with p63

The intracellular domains of Notch1 and 2 are functionally equivalent during development and carcinogenesis

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