The Jag2/Notch1 signaling axis promotes sebaceous gland differentiation and controls progenitor proliferation

Reviewer #1 (Public Review):

Summary:

In this study, Abidi and colleagues used Notch pathway-neutralizing antibodies to inhibit sebaceous glands in the skin. The authors find that blocking either the Notch1 receptor or the Jag2 ligand caused loss of the glands and increased retention of sebaceous progenitor cells. Moreover, these glands began to reappear 14 days after treatment.

Strengths:

Overall, this study definitively identifies the Notch receptor/ligand combination that maintains these glands in the adult. The manuscript is clearly written and the figures are beautifully made.

Weaknesses:

Minor text edits should be made.

Reviewer #2 (Public Review):

Summary:

In this report Abidi et al. use an antibody against Jag2, a Notch1 ligand, to inhibit its activity in skin. A single dose of this treatment leads to an impairment of sebocyte differentiation and an accumulation of basal sebocytes. Consistently Notch1 activity, measured as cleaved form of the Notch1 intracellular domain, is detected in basal sebocytes together with the expression of Jag2. Interestingly the phenotype caused by the antibody treatment is reversible.

Strengths:

The quality of the histological data with a clear phenotype, together with the quantification represents a solid base for the authors' claims.

This work identifies that the ligand Jag2 is the Notch1 ligand required for sebocyte differentiation.

From a therapeutic point of view, it is interesting that the treatment with anti-Jag2 is reversible.

Weaknesses:

The authors use a single approach to support their claims.

In this report, the analysis of the potential anti-Jag2 effect on the sebaceous ducts, the second cellular component of the sebaceous gland, is neglected.

Reviewer #3 (Public Review):

Abidi et al. investigated the role of Notch signalling for sebaceous gland differentiation and sebocyte progenitor proliferation in adult mouse skin. By injecting antagonising antibodies against different Notch receptors and ligands into mice, the authors identified that the Notch1 receptor and, to a lesser extent, Notch2 receptor, as well as the Notch ligand Jagged2, contribute to the regulation of sebaceous gland differentiation. In-situ hybridisation confirmed that treatment with anti-Jagged2 dramatically reduced the number of basal sebocytes staining for the transcriptionally active intracellular domain of Notch1. Loss of Notch activity in sebocyte progenitors robustly inhibited sebaceous gland differentiation. Under these conditions, the number of sebocyte progenitors marked by Lrig1 was not affected, while the number of proliferating basal sebocytes was increased. Upon recovery of Notch activity, sebaceous gland differentiation could likewise be recovered. By suggesting that Notch activity in sebocyte progenitors is required to balance proliferation and differentiation, these data bring valuable new and relevant findings for the skin field on the sebaceous gland homeostasis.

The data generally support the conclusions drawn by the authors; however, several additional experiments are required, and some aspects of the data analysis need to be clarified and improved to strengthen the manuscript.