Figure 9.
Figure 9. Summary of effects and working models. Hai1 can inhibit matriptase, matriptase can activate Par2, and loss of Hai1a function in zebrafish is associated with matriptase-dependent skin phenotypes. We characterized the role of Par2b in the two distinct epithelial layers that comprise skin, periderm, and basal layer in Hai1a-deficient zebrafish embryos. (A) Par2b is necessary for apical extrusion of apparently live cells from the periderm of Hai1a-deficient embryos and for apical extrusion of apoptotic cells in such embryos in which the EGFR Erbb2 is inhibited. Par2b also negatively regulates periderm cell proliferation. Mmp activity is necessary for the latter but not for apical extrusion. Erbb2 is necessary to prevent periderm cell apoptosis and associated additional extrusion events in Hai1a-deficient embryos and for high levels of cell proliferation in such embryos lacking Par2b. Combined deficiency or inhibition of Par2b and Erbb2 caused a nearly complete rescue of the Hai1a phenotype. At face value, these and other results suggest that matriptase-driven Par2b activity can drive apical cell extrusion and suppress proliferation in the periderm; that matriptase and Erbb2 promote periderm cell proliferation by a Par2b-independent mechanism; and that Erbb2 promotes survival of periderm cells in the setting of Hai1a-deficiency. (B) Par2b is necessary for and may drive E-cadherin redistribution, loss of stable cell–cell contacts, and increased cell movement and proliferation in the basal layer. These basal layer behaviors were partially dependent on Mmps and Erbb2. Thus, these molecules may mediate the effects of Par2b activation or play a permissive role. (C) Par2b is necessary for several phenotypes measured at the whole-embryo level: appearance of cell clusters on skin, leukocyte infiltration of the skin, and induction of il1b, mmp9, and mmp13 expression. The latter might contribute to phenotypes in A or B. The cell clusters almost certainly reflect basal cell swarming and areas of increased cell density and extrusion in periderm, which tended to be colocated. Collectively, these results are consistent with a model in which a local Hai1-matriptase-Par2 system may mediate responses to altered epithelial integrity.

Summary of effects and working models. Hai1 can inhibit matriptase, matriptase can activate Par2, and loss of Hai1a function in zebrafish is associated with matriptase-dependent skin phenotypes. We characterized the role of Par2b in the two distinct epithelial layers that comprise skin, periderm, and basal layer in Hai1a-deficient zebrafish embryos. (A) Par2b is necessary for apical extrusion of apparently live cells from the periderm of Hai1a-deficient embryos and for apical extrusion of apoptotic cells in such embryos in which the EGFR Erbb2 is inhibited. Par2b also negatively regulates periderm cell proliferation. Mmp activity is necessary for the latter but not for apical extrusion. Erbb2 is necessary to prevent periderm cell apoptosis and associated additional extrusion events in Hai1a-deficient embryos and for high levels of cell proliferation in such embryos lacking Par2b. Combined deficiency or inhibition of Par2b and Erbb2 caused a nearly complete rescue of the Hai1a phenotype. At face value, these and other results suggest that matriptase-driven Par2b activity can drive apical cell extrusion and suppress proliferation in the periderm; that matriptase and Erbb2 promote periderm cell proliferation by a Par2b-independent mechanism; and that Erbb2 promotes survival of periderm cells in the setting of Hai1a-deficiency. (B) Par2b is necessary for and may drive E-cadherin redistribution, loss of stable cell–cell contacts, and increased cell movement and proliferation in the basal layer. These basal layer behaviors were partially dependent on Mmps and Erbb2. Thus, these molecules may mediate the effects of Par2b activation or play a permissive role. (C) Par2b is necessary for several phenotypes measured at the whole-embryo level: appearance of cell clusters on skin, leukocyte infiltration of the skin, and induction of il1b, mmp9, and mmp13 expression. The latter might contribute to phenotypes in A or B. The cell clusters almost certainly reflect basal cell swarming and areas of increased cell density and extrusion in periderm, which tended to be colocated. Collectively, these results are consistent with a model in which a local Hai1-matriptase-Par2 system may mediate responses to altered epithelial integrity.

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