(A) In simple epithelia, TJs seal the apical end of the lateral cell membrane. The extracellular fluid is compartmentalized into two parts by TJs. (B) In the mammalian epidermis, the SC serves as an air-liquid interface barrier and protects the living layers from desiccation. TJs also seal the paracellular spaces between SG2 cells. TJs act as a liquid-liquid interface barrier in both simple and cornified stratified epithelia. LCs position their dendrites upward, ready to survey antigens upon sensing perturbation. (C) Terminal differentiation in relation to TJs. When SG3 cells differentiate into SG2 cells, they form TJs (i) and begin to secrete lamellar granules from their apical membranes (ii). SG1 cells appear to lose their TJs (iii) and then undergo final cornification (iv). Mature corneocytes are encapsulated in the cornified envelope (dark brown; v), and their intercellular spaces are filled with lipid lamellae (brown). Corneodesmosomes (green squares; vi) mediate intercorneocyte adhesion. KLKs secreted into the extracellular space are strictly limited to the extra-TJ environment. As the pH becomes acidic in the upper layers of the SC, KLKs are released from LEKTI and proteolyze corneodesmosomes, initiating desquamation (vii). Profilaggrin is a component of keratohyalin granules in the SG, is degraded into filaggrin monomers, possibly in SG1 cells, and is further degraded into NMFs in the upper SC (viii).