Ceramide Synthase 4 Regulates Stem Cell Homeostasis and Hair Follicle Cycling

Abstract

Ceramides are crucial for skin barrier function, but little is known about the regulation of epidermal appendages and whether stem cell populations that control their regeneration depend on specific ceramide species. Here we demonstrate that ceramide synthase 4 (CerS4) is highly expressed in the epidermis of adult mice where it is localized in the interfollicular epidermis and defined populations within the pilosebaceous unit. Inactivation of CerS4 in mice resulted in precocious activation of hair follicle bulge stem cells while expanding the Lrig1(+) junctional zone and sebaceous glands. This was preceded first by a decrease in bone morphogenetic protein (BMP) and a subsequent increase in Wnt signaling. This imbalance in quiescent versus activating signals likely promoted a prolonged anagen-like hair follicle state after the second catagen, which exhausted stem cells over time ultimately resulting in hair loss in aged mice. K14-Cre-mediated deletion of CerS4 revealed a similar phenotype, thus suggesting an epidermis intrinsic function of CerS4 in regulating the regeneration of the pilosebaceous unit. The data indicate that CerS4-directed epidermal ceramide composition is essential to control hair follicle stem and progenitor cell behavior potentially through its regulation of BMP and Wnt signaling.

TGF-β receptor I/II trafficking and signaling at primary cilia are inhibited by ceramide to attenuate cell migration and tumor metastasis

“…In the context of cancer, we observed that this increased ciliary TGF-β signaling and Shh activation enabled by the loss of CerS4 and long-chain ceramides in tumor cells promoted metastatic progression in mice. Our observations of alopecia and skin abnormalities in CerS4 −/− mice are consistent with other studies (46, 47), which link increased epidermal TβRI abundance with alopecia (48). Elsewhere, loss of Patched2 (Ptch2), a receptor protein that inhibits Shh signaling, has been associated with alopecia in Ptch2-deficient mice (63).…”

“…The genetic loss of CerS4 resulted in irreversible alopecia, which was concomitant with alterations in sebaceous glands and sebum contents in adult CerS4 −/− compared to wild-type CerS4 +/+ mice (fig. S3D), as previously reported (46, 47). …”

Ceramide synthesis regulates T cell activity and GVHD development

“…CerS3- Significance was determined by Student's t test. *P < 0.05, **P < 0.01, ***P < 0.001. generated ultra-long sphingolipids play key roles in the homeostasis of skin barrier function (34), whereas deficiency of CerS4 is associated with skin disorders such as irreversible alopecia (35,36).…”

Defective ceramide synthases in mice cause reduced amplitudes in electroretinograms and altered sphingolipid composition in retina and cornea

“…It was shown that CerS1 deficiency in mice causes progressive Purkinje cell loss and cerebellar shrinkage (Ginkel et al, 2012), CerS2-deficient mice suffer from hepatocarcinogenesis (Imgrund et al, 2009;Pewzner-Jung et al, 2010), myelin degeneration and microglia activation (Imgrund et al, 2009;Ben-David et al, 2011), and CerS4-deficient mice show progressive hair loss (Ebel et al, 2014;Peters et al, 2015). In CerS-deficient mice, the ceramide species for which the respective CerS is specific and the corresponding sphingolipid derivatives are strongly decreased.…”