Loss of ribosomal protein L11 affects zebrafish embryonic development through a p53-dependent apoptotic response.
Ribosome is responsible for protein synthesis in all organisms and ribosomal proteins (RPs) play important roles in the formation of a functional ribosome. L11 was recently shown to regulate p53 activity through a direct binding with MDM2 and abrogating the MDM2-induced p53 degradation in response to ribosomal stress. However, the studies were performed in cell lines and the significance of this tumor suppressor function of L11 has yet to be explored in animal models. To investigate the effects of the deletion of L11 and its physiological relevance to p53 activity, we knocked down the rpl11 gene in zebrafish and analyzed the p53 response. Contrary to the cell line-based results, our data indicate that an L11 deficiency in a model organism activates the p53 pathway. The L11-deficient embryos (morphants) displayed developmental abnormalities primarily in the brain, leading to embryonic lethality within 6-7 days post fertilization. Extensive apoptosis was observed in the head region of the morphants, thus correlating the morphological defects with apparent cell death. A decrease in total abundance of genes involved in neural patterning of the brain was observed in the morphants, suggesting a reduction in neural progenitor cells. Upregulation of the genes involved in the p53 pathway were observed in the morphants. Simultaneous knockdown of the p53 gene rescued the developmental defects and apoptosis in the morphants. These results suggest that ribosomal dysfunction due to the loss of L11 activates a p53-dependent checkpoint response to prevent improper embryonic development.
Chakraborty
Anirban
A
Frontier Science Research Center, University of Miyazaki, Miyazaki, Japan.
Uechi
Tamayo
T
Higa
Sayomi
S
Torihara
Hidetsugu
H
Kenmochi
Naoya
N
D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000235:genetics*; D004625:Embryo, Nonmammalian / Q000378:metabolism; D047108:Embryonic Development / Q000235:genetics; D009474:Neurons / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012269:Ribosomal Proteins / Q000235:genetics*; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics* / Q000378:metabolism; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism
D012333:RNA, Messenger; D012269:Ribosomal Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D029961:Zebrafish Proteins; C027624:ribosomal protein L11