Peter M. Elias

Spink5-deficient mice mimic Netherton syndrome through degradation of desmoglein 1 by epidermal protease hyperactivity

Mutations in SPINK5, encoding the serine protease inhibitor LEKTI, cause Netherton syndrome, a severe autosomal recessive genodermatosis. Spink5−/− mice faithfully replicate key features of Netherton syndrome, including altered desquamation, impaired keratinization, hair malformation and a skin barrier defect. LEKTI deficiency causes abnormal desmosome cleavage in the upper granular layer through degradation of desmoglein 1 due to stratum corneum tryptic enzyme and stratum corneum chymotryptic enzyme–like hyperactivity. This leads to defective stratum corneum adhesion and resultant loss of skin barrier function. Profilaggrin processing is increased and implicates LEKTI in the cornification process. This work identifies LEKTI as a key regulator of epidermal protease activity and degradation of desmoglein 1 as the primary pathogenic event in Netherton syndrome.

The Intercorneocyte Space

The vision of the stratum corneum as a dead, disorganized layer in various stages of desquamation, as seen in both light and transmission electron microscope images, is now known to be an artifact of tissue processing. Frozen sections of stratum comeum, swollen with dilute alkali, and viewed by either phase contrast [52], scanning electron microscopy [54], or by fluorescence microscopy after labeling with fluorescein [11] or 8-anilino-l-naphthalene sulfonic acid (ANS) [19], reveal the stratum corneum to be a latticework of polyhedral cells arranged as interlocked vertical columns. This morphological reappraisal, coupled with the biophysicists’ new appreciation for the barrier properties of the stratum corneum [4, 67, 77], has rekindled interest in the subcellular organization of this tissue (reviewed in [15, 16]). The major hypothesis that will be examined in this review depicts the stratum corneum as a two-compartment system of lipid-depleted cells surrounded by lipid-enriched intercellular domains. This model replaces the older view of the stratum corneum as a homogeneous sheet of filaments interspersed with lipid matrix [3, 13,30, 75]. We will summarize morphological, cytochemical, biochemical, and direct experimental evidence in support of this hypothesis, and will examine certain predictions based upon this two-compartment model.

Epidermal Cholesterol Sulfate and Steroid Sulfatase Activity and Recessive X-linked Ichthyosis

The ichthyoses are a group of inherited and acquired disorders of cornification characterized clinically by excessive accumulation of scale [7]. Although the pathophysiology of stratum corneum retention in these disorders is poorly understood, deranged lipid metabolism has been implicated in several instances (reviewed in Elias [2]). One enzyme of lipid metabolism, steroid sulfatase, is missing in placenta and cultured skin fibroblasts of patients with recessive x-linked ichthyosis (RXLI) [9, 12].

Did Hairlessness Stimulate an Increase in Hominin Brain Size? Insights from the Cutaneous Neurosensory Interface and Comparative Vertebrate Morphology

The basis for the late stages of brain growth in our immediate human ancestors is unknown, but generally attributed to the development of language associated with increasingly complex social settings. We present arguments for an additional or alternative potential contributor to endocranial expansion. As ancestral humans emerged from tropical forests into open savannahs, loss of their body hair facilitated the dissipation of body heat. But their newly-exposed cutaneous surfaces would have been bombarded by exogenous stimuli that could have stimulated an increase in brain size required to centrally process a plethora of new sensory information arriving from the periphery. Two lines of evidence support this hypothesis. First, the common embryologic origin of epidermis and central nervous system (CNS) from the primitive neuroectoderm, endowed the skin with a broad suite of neuro mechanisms that mirrors the CNS, including outward-facing ‘physical’ receptors that monitor changes in visual, acoustic and olfactory stimuli, as well as many neuromediators that impact memory, mood and wakefulness in the CNS. Second, two groups of marine organisms, cephalopods and electric fish, exhibit large brain: body mass ratios associated with heightened cutaneous sensory capabilities. Human nakedness also stimulated new psychosocial and stress responses, mediated by cutaneous oxytocin and glucocorticoids, respectively. Together, these insights suggest that the onset of hairlessness could have stimulated an increment of endocranial expansion, shortly before the emergence of modern humans.