p63 Mediates an Apoptotic Response to Pharmacological and Disease-Related ER Stress in the Developing Epidermis

• Published in: Developmental cell Vol. 21; no. 3; pp. 492 - 505
• Main Authors: Pyati, Ujwal J., Gjini, Evisa, Carbonneau, Seth, Lee, Jeong-Soo, Guo, Feng, Jette, Cicely A., Kelsell, David P., Look, A. Thomas
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Elsevier Inc 13.09.2011; Cell Press
• Subjects: Ageing, cell death; Animals; Apoptosis - drug effects; Apoptosis - genetics; Apoptosis - physiology; Apoptosis Regulatory Proteins - genetics; Biological and medical sciences; Brefeldin A - pharmacology; Cell differentiation, maturation, development, hematopoiesis; Cell physiology; Connexins - genetics; Connexins - metabolism; Endoplasmic Reticulum - drug effects; Endoplasmic Reticulum - metabolism; Enzyme Inhibitors - pharmacology; Epidermis - drug effects; Epidermis - growth & development; Epidermis - metabolism; Erythrokeratodermia Variabilis - genetics; Erythrokeratodermia Variabilis - metabolism; Fundamental and applied biological sciences. Psychology; Humans; Molecular and cellular biology; Phosphoproteins - metabolism; Protein Synthesis Inhibitors - pharmacology; Proto-Oncogene Proteins - genetics; Stress, Physiological; Thapsigargin - pharmacology; Trans-Activators - metabolism; Transcription, Genetic; Up-Regulation - physiology; Zebrafish Proteins - genetics; Zebrafish Proteins - metabolism; Development; Epidermis; Stress; Apoptosis
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2011.07.012

Endoplasmic reticulum (ER) stress triggers tissue-specific responses that culminate in either cellular adaptation or apoptosis, but the genetic networks distinguishing these responses are not well understood. Here we demonstrate that ER stress induced in the developing zebrafish causes rapid apoptosis in the brain, spinal cord, tail epidermis, lens, and epiphysis. Focusing on the tail epidermis, we uncover an apoptotic response that depends on Puma, but not on p53 or Chop. puma is transcriptionally activated during this ER stress response in a p53-independent manner, and is an essential mediator of epidermal apoptosis. We demonstrate that the p63 transcription factor is upregulated to initiate this apoptotic pathway and directly activates puma transcription in response to ER stress. We also show that a mutation of human Connexin 31, which causes erythrokeratoderma variabilis, induces ER stress and p63-dependent epidermal apoptosis in the zebrafish embryo, thus implicating this pathway in the pathogenesis of inherited disease. ► ER stress induces p53-independent apoptosis in the epidermis of zebrafish embryos ► This rapid ER stress-induced apoptotic axis depends on Puma and p63, but not Chop ► p63 directly activates puma expression in response to ER stress to trigger apoptosis ► p63 is also required for ER stress induced by an inherited Connexin 31 mutation