Department of Discovery Oncology, Genentech, San Francisco, United States.
Department of Research Pathology, Genentech, San Francisco, United States.
Elife. 2024 Nov 25;13:RP98747. doi: 10.7554/eLife.98747.
The sebaceous gland (SG) is a vital appendage of the epidermis, and its normal homeostasis and function is crucial for effective maintenance of the skin barrier. Notch signaling is a well-known regulator of epidermal differentiation, and has also been shown to be involved in postnatal maintenance of SGs. However, the precise role of Notch signaling in regulating SG differentiation in the adult homeostatic skin remains unclear. While there is evidence to suggest that Notch1 is the primary Notch receptor involved in regulating the differentiation process, the ligand remains unknown. Using monoclonal therapeutic antibodies designed to specifically inhibit of each of the Notch ligands or receptors, we have identified the Jag2/Notch1 signaling axis as the primary regulator of sebocyte differentiation in mouse homeostatic skin. Mature sebocytes are lost upon specific inhibition of the Jag2 ligand or Notch1 receptor, resulting in the accumulation of proliferative stem/progenitor cells in the SG. Strikingly, this phenotype is reversible, as these stem/progenitor cells re-enter differentiation when the inhibition of Notch activity is lifted. Thus, Notch activity promotes correct sebocyte differentiation, and is required to restrict progenitor proliferation.
皮脂腺 (SG) 是表皮的重要附属物，其正常的动态平衡和功能对于有效维持皮肤屏障至关重要。Notch 信号通路是表皮分化的已知调节剂，也被证明参与了 SG 的出生后维持。然而，Notch 信号通路在调节成人稳态皮肤中 SG 分化的确切作用仍不清楚。虽然有证据表明 Notch1 是参与调节分化过程的主要 Notch 受体，但配体仍然未知。使用设计用于特异性抑制每个 Notch 配体或受体的单克隆治疗性抗体，我们已经确定 Jag2/Notch1 信号轴是调节小鼠稳态皮肤中皮脂腺分化的主要调节剂。特异性抑制 Jag2 配体或 Notch1 受体可导致成熟的皮脂腺丢失，导致 SG 中增殖性干细胞/祖细胞的积累。引人注目的是，这种表型是可逆的，因为当 Notch 活性的抑制解除时，这些干细胞/祖细胞重新进入分化。因此，Notch 活性促进了正确的皮脂腺分化，并需要限制祖细胞的增殖。
