Nuclear encoded mitochondrial ribosomal proteins are required to initiate gastrulation

• DOI: 10.1242/dev.188714
• Publication Date: 2020-05-06T15:35:11Z
• Authors: Agnes Cheong; Danielle Archambault; Rinat Degani; Elizabeth Iverson; Kimberly Tremblay; Jesse Mager
• Keywords: Male; Mice, Knockout; Ribosomal Proteins; 0301 basic medicine; 0303 health sciences; Gastrulation; Embryonic Development; Cell Cycle Checkpoints; 7. Clean energy; Mitochondria; Mice, Inbred C57BL; Mitochondrial Proteins; Mitochondrial Ribosomes; Gene Knockout Techniques; Mice; 03 medical and health sciences; Phenotype; Animals; Female

Mitochondria are essential for energy production and while they have their own genome, many nuclear-encoded mitochondrial ribosomal proteins (MRPs) are required for proper function of the organelle. Although mutations in MRPs have been associated with human diseases, little is known about their role during development. Presented here are the null phenotypes for 21 nuclear encoded mitochondrial proteins and in-depth characterization of five MRP mutants - Mrpl3, Mrpl22, Mrpl44, Mrps18c and Mrps22. Loss of each MRP results in successful implantation and egg-cylinder formation but then severe developmental delay and failure to initiate gastrulation by embryonic day (E) 7.5. The robust and similar single knockout phenotypes are somewhat surprising given there are over 70 MRPs and suggest little functional redundancy. Metabolic analysis reveals that Mrp knockout embryos produce significantly less ATP than controls, indicating compromised mitochondrial function. Histological and immunofluorescence analyses indicate abnormal organelle morphology and stalling at the G2/M checkpoint in Mrp null cells. The nearly identical pre-gastrulation phenotype observed for many different nuclear-encoded mitochondrial protein knockouts hints that distinct energy systems are critical at specific timepoints during mammalian development.