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

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

  • Dev Cell. 2021 Dec 20;56(24):3334-3348.e6. doi: 10.1016/j.devcel.2021.11.020.
Chang Xie 1 Shaun R Abrams 1 Vicente Herranz-Pérez 2 Jose Manuel García-Verdugo 3 Jeremy F Reiter 4
Affiliations

Affiliations

  • 1 Department of Biochemistry and Biophysics, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA.
  • 2 Cavanilles Institute of Biodiversity and Evolutionary Biology, University of Valencia, Valencia, Spain; Predepartamental Unit of Medicine, Jaume I University, Castelló de la Plana, Spain.
  • 3 Cavanilles Institute of Biodiversity and Evolutionary Biology, University of Valencia, Valencia, Spain.
  • 4 Department of Biochemistry and Biophysics, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA. Electronic address: jeremy.reiter@ucsf.edu.
Abstract

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.

Keywords

ERK; apoptosis; centriole; endoderm; intestine development; lung branching; p53.

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