Consequences of depleted SERCA2-gated calcium stores in the skin.
Sarco(endo)plasmic reticulum Ca2+-ATPase isoform 2 (SERCA2) pumps belong to the family of Ca2+-ATPases responsible for the maintenance of calcium in the endoplasmic reticulum. In epidermal keratinocytes, SERCA2-controlled calcium stores are involved in cell cycle exit and onset of terminal differentiation. Hence, their dysfunction was thought to provoke impaired keratinocyte cohesion and hampered terminal differentiation. Here, we assessed cultured keratinocytes and skin biopsies from a canine family with an inherited skin blistering disorder. Cells from lesional and phenotypically normal areas of one of these dogs revealed affected calcium homeostasis due to depleted SERCA2-gated stores. In phenotypically normal patient cells, this defect compromised upregulation of p21(WAF1) and delayed the exit from the cell cycle. Despite this abnormality it failed to impede the terminal differentiation process in the long term but instead coincided with enhanced apoptosis and appearance of chronic wounds, suggestive of secondary mutations. Collectively, these findings provide the first survey on phenotypic consequences of depleted SERCA-gated stores for epidermal homeostasis that explain how depleted SERCA2 calcium stores provoke focal lesions rather than generalized dermatoses, a phenotype highly reminiscent of the human genodermatosis Darier disease.
Müller
Eliane J
EJ
Vetsuisse Faculty, Institute of Animal Pathology, University of Bern, Bern, Switzerland. eliane.mueller@itpa.unibe.ch
Caldelari
Reto
R
Kolly
Carine
C
Williamson
Lina
L
Baumann
Dominique
D
Richard
Gabriele
G
Jensen
Pamela
P
Girling
Peter
P
Delprincipe
Franco
F
Wyder
Marianne
M
Balmer
Vreni
V
Suter
Maja M
MM
D000818:Animals; D001768:Blister / Q000235:genetics / Q000473:pathology*; D000252:Calcium-Transporting ATPases / Q000235:genetics*; D002448:Cell Adhesion; D002453:Cell Cycle; D002454:Cell Differentiation / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D007644:Darier Disease / Q000235:genetics* / Q000473:pathology; D004285:Dogs; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004817:Epidermis / Q000737:chemistry / Q000473:pathology*; D006801:Humans; D007365:Intercellular Junctions / Q000235:genetics; D015603:Keratinocytes / Q000737:chemistry / Q000473:pathology; D019394:Ki-67 Antigen / Q000032:analysis; D008297:Male; D009154:Mutation; D010641:Phenotype; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D015854:Up-Regulation
D050759:Cyclin-Dependent Kinase Inhibitor p21; D019394:Ki-67 Antigen; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506946:ATP2A2 protein, human; D000252:Calcium-Transporting ATPases