No abstract

The stratum corneum as the outermost epidermal layer protects against exsiccation and infection. Both the underlying cornified envelope (CE) and the intercellular lipid matrix contribute essentially to these two main protective barriers. Epidermis-unique ceramides with ultra-long-chain acyl moities (ULC-Cers) are key components of extracellular lipid lamellae (ELL) and are bound to CE proteins, thereby contributing to the cornified lipid envelope (CLE). Here, we identified human and mouse ceramide synthase 3 (CerS3), among CerS1-6, to be exclusively required for the ULC-Cer synthesis in vitro and of mouse CerS3 in vivo. Deficiency of CerS3 in mice results in complete loss of ULC-Cers (≥C26), lack of continuous ELL and a non-functional CLE. Consequently, newborn mutant mice die shortly after birth from transepidermal water loss. Mutant skin is prone to Candida albicans infection highlighting ULC-Cers to be pivotal for both barrier functions. Persistent periderm, hyperkeratosis and deficient cornification are hallmarks of mutant skin demonstrating loss of Cers to trigger a keratinocyte maturation arrest at an embryonic pre-barrier stage.

Body weight and energy homeostasis are regulated by leptin receptor interactions with gangliosides, a class of plasma membrane lipids, in forebrain neurons of mice.

Ceramides are vital components of the water barrier in mammalian skin. Epidermis-specific, a major ceramide portion contains -hydroxy very long chain fatty acids (C30 -C36). These -hydroxy ceramides (Cers) are found in the extracellular lamellae of the stratum corneum either as linoleic acyl esters or protein bound. Glucosylceramide is the major glycosphingolipid of the epidermis. Synthesized from ceramide and UDPglucose, it is thought to be itself an intracellular precursor and carrier for extracellular -hydroxy ceramides. To investigate whether GlcCer is an obligatory intermediate in ceramide metabolism to maintain epidermal barrier function, a mouse with an epidermis-specific glucosylceramide synthase (Ugcg) deficiency has been generated. Four days after birth animals devoid of GlcCer synthesis in keratinocytes showed a pronounced desquamation of the stratum corneum and extreme transepidermal water loss leading to death. The stratum corneum appeared as a thick unstructured mass. Lamellar bodies of the stratum granulosum did not display the usual ordered inner structure and were often irregularly arranged. Although the total amount of epidermal protein-bound ceramides remained unchanged, epidermal-free -hydroxy ceramides increased 4-fold and -hydroxy sphingomyelins, almost not detectable in wild type epidermis, emerged in quantities comparable with lost GlcCer. We conclude that the transient formation of GlcCer is vital for a regular arrangement of lipids and proteins in lamellar bodies and for the maintenance of the epidermal barrier.Glucosylceramide synthase (Ugcg), catalyzing the initial step of glycosphingolipid synthesis (see Fig. 1A), is vital during embryogenesis as revealed by systemic deletion in mice (1). To investigate the different functions of glucosylceramide (GlcCer) 4 -based glycolipids in vivo, cell-specific deletions of this enzyme are indispensable. Successful deletion of glucosylceramide synthase in neural cells led to loss of brain gangliosides. Nevertheless, mice were born developing severe dysfunctions postnatally (2, 3). In this report we focus on the function of GlcCer in skin.Land dwelling animals have a water and electrolyte barrier in the skin to prevent dehydration and electrolyte disturbances. Both membrane proteins of keratinocytes and lipids generated in the epidermis are important for maintenance of the skin barrier and, therefore, for the impermeability of the skin to water. Ceramides (Cers) constitute a major component of the lipid barrier. They are synthesized by amidation of sphingoid bases with long chain fatty acids at the endoplasmic reticulum. Conversion into GlcCer by Ugcg takes place at the cytoplasmic surface of the Golgi apparatus (4, 5).GlcCers are the dominant glycosphingolipids of the epidermis and constitute ϳ4% of the total epidermal lipid mass (6). They are thought to act as an intracellular carrier for secreted ceramides and constitute the main components of lamellar bodies (LBs) (7-9). LBs are found in cells of the upper stratum granulosum and are extruded...