Growth Retardation, Loss of Desmosomal Adhesion, and Impaired Tight Junction Function Identify a Unique Role of Plakophilin 1 In Vivo

Abstract

Desmosomes mediate strong intercellular adhesion through desmosomal cadherins that interact with intracellular linker proteins including plakophilins (PKPs) 1-3 to anchor the intermediate filaments. PKPs show overlapping but distinct expression patterns in the epidermis. So far, the contribution of individual PKPs in differentially regulating desmosome function is incompletely understood. To resolve the role of PKP1 we ablated the PKP1 gene. Here, we report that PKP1(-/-) mice were born at the expected mendelian ratio with reduced birth weight, but they otherwise appeared normal immediately after birth. However, their condition rapidly declined, and the mice died within 24 hours, developing fragile skin with lesions in the absence of obvious mechanical trauma. This was accompanied by sparse and small desmosomes. Newborn PKP1(-/-) mice showed disturbed tight junctions with an impaired inside-out barrier, whereas the outside-in barrier was unaffected. Keratinocytes isolated from these mice showed strongly reduced intercellular cohesion, delayed tight junction formation, and reduced transepithelial resistance and reduced proliferation rates. Our study shows a nonredundant and essential role of PKP1 in desmosome and tight junction function and supports a role of PKP1 in growth control, a function that is crucial in wound healing and epidermal carcinogenesis.

Phosphorylation of Pkp1 by RIPK4 regulates epidermal differentiation and skin tumorigenesis

“…In particular, desmosomal proteins were identified as a significant part of this enriched group of phosphorylated proteins during differentiation (Fig 1C). Consistently, a recent study with complete KO of Pkp1 in mice shows profound cell junctional aberrancy and expanded expression of Krt-5 and Krt-14 toward suprabasal layers in the KO skin (Rietscher et al, 2016). The changes were not due to altered expression level of Pkp1, as immunoblot analysis revealed comparable level of Pkp1 in both undifferentiated and differentiated (12 h) keratinocytes ( Fig EV1E).…”

“…ZO-1 (zonula occudens-1) staining in Pkp1 KO skin was significantly reduced and discontinuous comparing with the WT counterpart ( Fig EV2G). These results are also consistent with the recent report that complete KO of Pkp1 in mice leads to profound cell junctional aberrancy in vivo (Rietscher et al, 2016).…”

“…However, loss of Pkp1 led to more diffusive DSG1 staining in the regenerated skin, suggesting potential defects in desmosome formation (Fig EV2G). These results are also consistent with the recent report that complete KO of Pkp1 in mice leads to profound cell junctional aberrancy in vivo (Rietscher et al, 2016). ZO-1 (zonula occudens-1) staining in Pkp1 KO skin was significantly reduced and discontinuous comparing with the WT counterpart ( Fig EV2G).…”

“…A recent study demonstrated that complete KO of Pkp1 in mice leads to growth retardation and perinatal lethality (Rietscher et al, 2016). In this report, we present compelling evidence that loss of Pkp1 leads to significant defects in epidermal differentiation, and its role in this process is dependent upon RIPK4-mediated phosphorylation of its N-terminal head domain.…”

Ectodermal dysplasia–skin fragility syndrome resulting from a new atypical homozygous cryptic acceptor splice site mutation in PKP1

“…PKP1 has an important role in providing stable cohesion to keratinocytes throughout the spinous layer to resist mechanical stress [7], as well as contributing to tight junction biology with implications for the control of cell and tissue growth [8]. Moreover, PKP1 has dynamic roles in cell signaling, for example through interactions with proteins such as focal adhesion kinase [9].…”