Barrier activity of skin and internal barrier-forming epithelial linings are conferred by a lipid-corneocyte structure (stratum corneum in skin).The integrity of the corneocytes depends on the outer cornified envelope and is essential for maintenance of barrier function. During epidermal development and differentiation, proteins are sequentially incorporated into the envelope via action of epidermal transglutaminases in a well documented process. However, recent knockouts of major cornified envelope constituents have failed to disrupt barrier function significantly, suggesting that additional unidentified components are involved. We report a new gene cluster in the epidermal differentiation complex at human 1q21 encoding a family of 18 proteins that are substrates for epidermal transglutaminases. These proteins incorporate into the cornified envelope late in development and late in the process of envelope maturation during epidermal differentiation. The genes cluster within the epidermal differentiation complex according to expression pattern, i.e., epidermally expressed proteins cluster together while proteins from internal barrier-forming epithelia also cluster. We propose that these proteins modulate barrier activity over the surface of the animal, in a manner analogous to that proposed for the well characterized cornified envelope precursors, the small proline-rich proteins. To emphasize the incorporation of these proteins late in envelope assembly, we call the human proteins late envelope proteins.

An organism's outermost covering, the integument, has evolved to fulfil a diverse range of functions. Skin provides a physical barrier, an environment for immunological surveillance, and also performs a range of sensory, thermoregulatory and biosynthetic functions. Examination of the skin of limb digits reveals a range of skin types including the thickened hairless epidermis of the toe pads (palmar or plantar epidermis) and thinner epidermis between the hair follicles (interfollicular epidermis) of hairy skin. An important developmental function of skin is to give rise to a diverse group of appendages including hair follicles, with associated sebaceous glands (or feathers and scales in chick), eccrine sweat glands and the nail. A key question is how does this morphological variety arise from the single-layered epithelium covering embryonic limb buds? This review will attempt to address this question by linking the extensive morphological /anatomical data on maturation of epidermis and its appendages with (1) current research into the range, plasticity and location of the putative epidermal stems cells; (2) molecular/microenvironmental regulation of epidermal stem cell lineages and lineage choice; and (3) regulation of the differentiation pathways, focusing on differentiation of the interfollicular epidermis.Key words appendages; cell lineages; ectoderm, skin barrier; skin development; terminal differentiation. Epidermis as a structural barrier organNormal adult skin comprises a thin surface epidermis nourished and maintained by a thicker dermis. Epidermis of the limb gives rise to a range of skin types (palmar, plantar and interfollicular epidermis) and varied appendages (including hair follicles, sebaceous glands, eccrine sweat glands and the nail) (Fig. 1). Epidermis' primary role is protective and it provides protection largely through construction of an elaborate and highly organized outer surface, the stratum corneum. Stratum corneum is the primary interface and barrier between an organism and its outer environment and acts to prevent desiccation, toxin entry and microbial infection.A key feature of this protective outer layer is that it is continually shed and replenished by underlying keratinocytes, so that damaged, infected or contaminated cells are removed from the body and the barrier is maintained. The stem cells necessary for maintenance of this cycling structure are located in the basal stratum of epidermis ( Fig. 2) and in specialized compartments of skin appendages like hair follicles (see reviews by Fuchs & Raghavan, 2002;Watt, 2002). Proliferative keratinocytes (transit or transiently amplifying cells) derived from these stem cells also reside in this basal layer (see Stratum corneum consists of anucleate, flattened keratinocytes embedded in a lipid matrix ( Fig. 2; reviewed by Kalinin et al. 2001 The basement membrane separates the dermis (primarily consisting of fibroblasts, elastin and collagen) and the overlying epidermis. The epidermis comprises four distinct layers, basal, spino...

Members of the Sox gene family encode transcription factors that have diverse and important functions during development. We have recently described the cloning of chick and mouse Sox14 and the expression of these genes in a population of ventral interneurons in the embryonic spinal cord. We report here the cloning and sequencing of the human orthologue of Sox14. Human SOX14 shows remarkable sequence conservation compared with orthologues from other vertebrate species and probably mirrors the expression of these genes in the developing brain and spinal cord. Using radiation hybrid mapping and fluorescence in situ hybridisation, we have localised SOX14 close to the sequence tagged site D3S1576 on human chromosome 3q23. Three congenital disorders have been localised to this region: blepharophimosis-ptosis-epicanthus inversus syndrome (BPES), Charcot-Marie-Tooth neuropathy type IIB (CMT2B) and Mobius syndrome type 2 (MBS2). We have found that SOX14 is unlikely to be involved in any of these disorders because of the position of SOX14 proximal to a BPES breakpoint and the lack of SOX14 coding region alterations in BPES, CMT2B and MBS2 patients.

BB2603 is a nano‐formulation of the antifungal drug terbinafine with the polymer polyhexamethylene biguanide (PHMB) as an excipient to enhance solubility and drug delivery to skin and nails. BB2603 is delivered topically using a low‐velocity spray. It is being developed in different strength formulations for the treatment of fungal infections of the nail and skin, including onychomycosis and tinea pedis, with BB2603‐1 (0.01% terbinafine) tested in the present trial. The aim of this study was to assess systemic exposure, safety and tolerability of BB2603‐1 compared with Lamisil® AT 1% spray and BB2603‐1 vehicle control in onychomycosis and tinea pedis. Preliminary mycological and clinical activity were also investigated. This was a single‐centre Phase 1/2, randomised, partially blinded, active‐ and vehicle‐controlled, parallel‐group trial in 46 subjects with onychomycosis associated with tinea pedis. Part 1 investigated BB2603‐1 versus Lamisil AT 1% spray and BB2603‐1 vehicle (4 weeks treatment). Part 2 investigated BB2603‐1 versus BB2603‐1 vehicle (additional 48 weeks treatment). No measurable systemic exposure of terbinafine was shown over 52 weeks of treatment with BB2603‐1. BB2603‐1 had an excellent safety and tolerability profile with no drug‐related safety findings and no evidence of skin sensitisation. BB2603‐1 showed preliminary evidence of anti‐dermatophyte activity, demonstrated by a reduction in dermatophyte positive cultures and a reduction in microscopic evidence of dermatophytes. The pharmacokinetic, safety and efficacy data from this trial support further development of the topical terbinafine‐based nano‐formulation BB2603 in fungal infections of the skin and nail, including onychomycosis and tinea pedis.

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