Endoderm development requires centrioles to restrain p53-mediated apoptosis in the absence of ERK activity

• Published in: Developmental cell 2021-12, Vol.56 (24), p.3334-3348.e6
• Main Authors: Xie, Chang, Abrams, Shaun R., Herranz-Pérez, Vicente, García-Verdugo, Jose Manuel, Reiter, Jeremy F.
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Cell Survival; centriole; Centrioles - metabolism; endoderm; Endoderm - embryology; Endoderm - metabolism; Epithelial Cells - metabolism; ERK; Extracellular Signal-Regulated MAP Kinases - metabolism; intestine development; Intestines - growth & development; Lung - embryology; lung branching; Mice; Mice, Inbred C57BL; Microtubule-Associated Proteins - metabolism; Morphogenesis; p53; SOXB1 Transcription Factors - metabolism; Stem Cells - metabolism; Tumor Suppressor Protein p53 - metabolism
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2021.11.020

Centrioles comprise the heart of centrosomes, microtubule-organizing centers. To study the function of centrioles in lung and gut development, we genetically disrupted centrioles throughout the mouse endoderm. Surprisingly, removing centrioles from the endoderm did not disrupt intestinal growth or development but blocked lung branching. In the lung, acentriolar SOX2-expressing airway epithelial cells apoptosed. Loss of centrioles activated p53, and removing p53 restored survival of SOX2-expressing cells, lung branching, and mouse viability. To investigate how endodermal p53 activation specifically killed acentriolar SOX2-expressing cells, we assessed ERK, a prosurvival cue. ERK was active throughout the intestine and in the distal lung buds, correlating with tolerance to centriole loss. Pharmacologically inhibiting ERK activated apoptosis in acentriolar cells, revealing that ERK activity protects acentriolar cells from apoptosis. Therefore, centrioles are largely dispensable for endodermal growth and the spatial distribution of ERK activity in the endoderm shapes the developmental consequences of centriolar defects and p53 activation. [Display omitted] •Endodermal centrioles are critical for lung branching but not for intestine development•Centriole loss activates p53 to induce apoptosis in lung SOX2-expressing cells•ERK activity throughout the small intestine protects it from p53-mediated apoptosis•A gradient of ERK activity in the lungs shapes which cells die to block branching Chang et al. show that endoderm centrioles are dispensable for intestinal development but essential for lung branching. Throughout both intestine and lungs, loss of centrioles activates p53, but the lack of centrioles induces apoptosis only in domains of low ERK signaling.