Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli County, Taiwan, Republic of China.
PLoS One. 2011 Jan 18;6(1):e15842. doi: 10.1371/journal.pone.0015842.
Notch signaling involves ligand-receptor interactions through direct cell-cell contact. Multiple Notch receptors and ligands are expressed in the epidermis and hair follicles during embryonic development and the adult stage. Although Notch signaling plays an important role in regulating differentiation of the epidermis and hair follicles, it remains unclear how Notch signaling participates in late-stage epidermal differentiation and postnatal hair cycle homeostasis.
We applied Cre/loxP system to generate conditional gene targeted mice that allow inactivation of critical components of Notch signaling pathway in the skin. Rbpj, the core component of all four Notch receptors, and Pofut1, an essential factor for ligand-receptor interactions, were inactivated in hair follicle lineages and suprabasal layer of the epidermis using the Tgfb3-Cre mouse line. Rbpj conditional inactivation resulted in granular parakeratosis and reactive epidermal hyperplasia. Pofut1 conditional inactivation led to ultrastructural abnormalities in the granular layer and altered filaggrin processing in the epidermis, suggesting a perturbation of the granular layer differentiation. Disruption of Pofut1 in hair follicle lineages resulted in aberrant telogen morphology, a decrease of bulge stem cell markers, and a concomitant increase of K14-positive keratinocytes in the isthmus of mutant hair follicles. Pofut1-deficent hair follicles displayed a delay in anagen re-entry and dysregulation of proliferation and apoptosis during the hair cycle transition. Moreover, increased DNA double stand breaks were detected in Pofut1-deficent hair follicles, and real time PCR analyses on bulge keratinocytes isolated by FACS revealed an induction of DNA damage response and a paucity of DNA repair machinery in mutant bulge keratinocytes.
our data reveal a role for Notch signaling in regulating late-stage epidermal differentiation. Notch signaling is required for postnatal hair cycle homeostasis by maintaining proper proliferation and differentiation of hair follicle stem cells.
Notch 信号通过直接的细胞间接触涉及配体-受体相互作用。在胚胎发育和成年阶段，多个 Notch 受体和配体在表皮和毛囊中表达。虽然 Notch 信号在调节表皮和毛囊的分化中起着重要作用，但 Notch 信号如何参与晚期表皮分化和出生后毛发生长周期稳态仍不清楚。
我们应用 Cre/loxP 系统生成条件性基因靶向小鼠，使 Notch 信号通路的关键组成部分在皮肤中失活。使用 Tgfb3-Cre 小鼠品系，在毛囊谱系和表皮的基底层中使 Notch 受体的核心组成部分 Rbpj 和配体-受体相互作用的必需因子 Pofut1 失活。Rbpj 条件性失活导致颗粒性角化不全和表皮反应性增生。Pofut1 条件性失活导致表皮颗粒层的超微结构异常和丝状角蛋白加工改变，提示颗粒层分化受到干扰。毛囊谱系中 Pofut1 的破坏导致异常的休止期形态，毛囊隆起干细胞标志物减少，同时突变毛囊的峡部 K14 阳性角质形成细胞增加。Pofut1 缺陷的毛囊显示出进入生长期的延迟，以及在毛发生长周期转换过程中增殖和凋亡的失调。此外，在 Pofut1 缺陷的毛囊中检测到 DNA 双链断裂增加，并且通过 FACS 分离的隆起角质形成细胞的实时 PCR 分析显示突变隆起角质形成细胞中 DNA 损伤反应的诱导和 DNA 修复机制的缺乏。
我们的数据揭示了 Notch 信号在调节晚期表皮分化中的作用。Notch 信号通过维持毛囊干细胞的适当增殖和分化，对出生后毛发生长周期稳态是必需的。
