Submitted January 9, 2008
Accepted April 5, 2008
Ribosomal protein S19 deficiency in zebrafish leads to developmental abnormalities and defective erythropoiesis through activation of p53 protein family
Nadia Danilova, Kathleen M Sakamoto, and Shuo Lin*
Department of Molecular, Cell & Developmental Biology (MCDB), Universty of California Los Angeles, Los Angeles, CA, United States
Division of Hematology/Oncology, Department of Pediatrics, Gwynne Hazen Cherry Memorial Laboratories and Mattel Children's Hospital, Los Angeles, CA, United States
* Corresponding author; email: shuolin{at}ucla.edu.
Mutations in several ribosomal proteins (RPs) lead to Diamond-Blackfan Anemia (DBA), a syndrome characterized by defective erythropoiesis, congenital anomalies, and increased frequency of cancer. RPS19 is the most frequently mutated RP in DBA. RPS19 deficiency impairs ribosomal biogenesis, but how this leads to DBA or cancer remains unknown. We have found that RPS19 deficiency in zebrafish results in hematopoietic and developmental abnormalities resembling DBA. Our data suggest that the RPS19-deficient phenotype is mediated by dysregulation of 
Np63 and p53. During gastrulation, Np63 is required for specification of non-neural ectoderm and its upregulation suppresses neural differentiation thus contributing to brain/craniofacial defects. In RPS19-deficient embryos, Np63 is induced in erythroid progenitors and may contribute to blood defects. We have shown that suppression of p53 and Np63 alleviates the RPS19-deficient phenotypes. Mutations in other ribosomal proteins such as S8, S11, and S18 also lead to upregulation of p53 pathway suggesting it is a common response to ribosomal protein deficiency. Our finding provides new insights into pathogenesis of DBA. Ribosomal stress syndromes represent a broader spectrum of human congenital diseases caused by genotoxic stress; therefore imbalance of p53 family members may become a new target for therapeutics.
