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RPSA, a candidate gene for isolated congenital asplenia, is required for pre-rRNA processing and spleen formation in Xenopus.
Development 2018; 145(20)D

Abstract

A growing number of tissue-specific inherited disorders are associated with impaired ribosome production, despite the universal requirement for ribosome function. Recently, mutations in RPSA, a protein component of the small ribosomal subunit, were discovered to underlie approximately half of all isolated congenital asplenia cases. However, the mechanisms by which mutations in this ribosome biogenesis factor lead specifically to spleen agenesis remain unknown, in part due to the lack of a suitable animal model for study. Here we reveal that RPSA is required for normal spleen development in the frog, Xenopus tropicalis Depletion of Rpsa in early embryonic development disrupts pre-rRNA processing and ribosome biogenesis, and impairs expression of the key spleen patterning genes nkx2-5, bapx1 and pod1 in the spleen anlage. Importantly, we also show that whereas injection of human RPSA mRNA can rescue both pre-rRNA processing and spleen patterning, injection of human mRNA bearing a common disease-associated mutation cannot. Together, we present the first animal model of RPSA-mediated asplenia and reveal a crucial requirement for RPSA in pre-rRNA processing and molecular patterning during early Xenopus development.

Authors+Show Affiliations

Pediatric Genomics Discovery Program, Departments of Pediatrics and Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06510, USA.Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06510, USA.Pediatric Genomics Discovery Program, Departments of Pediatrics and Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06510, USA.Pediatric Genomics Discovery Program, Departments of Pediatrics and Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06510, USA.Pediatric Genomics Discovery Program, Departments of Pediatrics and Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06510, USA.Pediatric Genomics Discovery Program, Departments of Pediatrics and Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06510, USA.Pediatric Genomics Discovery Program, Departments of Pediatrics and Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06510, USA.Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06510, USA susan.baserga@yale.edu mustafa.khokha@yale.edu. Departments of Molecular Biophysics and Biochemistry, and Therapeutic Radiology, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06510, USA.Pediatric Genomics Discovery Program, Departments of Pediatrics and Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06510, USA susan.baserga@yale.edu mustafa.khokha@yale.edu. Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06510, USA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

30337486

Citation

Griffin, John N., et al. "RPSA, a Candidate Gene for Isolated Congenital Asplenia, Is Required for pre-rRNA Processing and Spleen Formation in Xenopus." Development (Cambridge, England), vol. 145, no. 20, 2018.
Griffin JN, Sondalle SB, Robson A, et al. RPSA, a candidate gene for isolated congenital asplenia, is required for pre-rRNA processing and spleen formation in Xenopus. Development. 2018;145(20).
Griffin, J. N., Sondalle, S. B., Robson, A., Mis, E. K., Griffin, G., Kulkarni, S. S., ... Khokha, M. K. (2018). RPSA, a candidate gene for isolated congenital asplenia, is required for pre-rRNA processing and spleen formation in Xenopus. Development (Cambridge, England), 145(20), doi:10.1242/dev.166181.
Griffin JN, et al. RPSA, a Candidate Gene for Isolated Congenital Asplenia, Is Required for pre-rRNA Processing and Spleen Formation in Xenopus. Development. 2018 10 18;145(20) PubMed PMID: 30337486.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - RPSA, a candidate gene for isolated congenital asplenia, is required for pre-rRNA processing and spleen formation in Xenopus. AU - Griffin,John N, AU - Sondalle,Samuel B, AU - Robson,Andrew, AU - Mis,Emily K, AU - Griffin,Gerald, AU - Kulkarni,Saurabh S, AU - Deniz,Engin, AU - Baserga,Susan J, AU - Khokha,Mustafa K, Y1 - 2018/10/18/ PY - 2018/04/11/received PY - 2018/09/13/accepted PY - 2018/10/20/entrez PY - 2018/10/20/pubmed PY - 2019/2/13/medline KW - Asplenia KW - RPSA KW - Ribosomopathy KW - Xenopus KW - rRNA processing JF - Development (Cambridge, England) JO - Development VL - 145 IS - 20 N2 - A growing number of tissue-specific inherited disorders are associated with impaired ribosome production, despite the universal requirement for ribosome function. Recently, mutations in RPSA, a protein component of the small ribosomal subunit, were discovered to underlie approximately half of all isolated congenital asplenia cases. However, the mechanisms by which mutations in this ribosome biogenesis factor lead specifically to spleen agenesis remain unknown, in part due to the lack of a suitable animal model for study. Here we reveal that RPSA is required for normal spleen development in the frog, Xenopus tropicalis Depletion of Rpsa in early embryonic development disrupts pre-rRNA processing and ribosome biogenesis, and impairs expression of the key spleen patterning genes nkx2-5, bapx1 and pod1 in the spleen anlage. Importantly, we also show that whereas injection of human RPSA mRNA can rescue both pre-rRNA processing and spleen patterning, injection of human mRNA bearing a common disease-associated mutation cannot. Together, we present the first animal model of RPSA-mediated asplenia and reveal a crucial requirement for RPSA in pre-rRNA processing and molecular patterning during early Xenopus development. SN - 1477-9129 UR - https://www.unboundmedicine.com/medline/citation/30337486/RPSA_a_candidate_gene_for_isolated_congenital_asplenia_is_required_for_pre_rRNA_processing_and_spleen_formation_in_Xenopus_ L2 - http://dev.biologists.org/cgi/pmidlookup?view=long&pmid=30337486 DB - PRIME DP - Unbound Medicine ER -