Format

Send to

Choose Destination
Hum Mol Genet. 2018 May 10. doi: 10.1093/hmg/ddy172. [Epub ahead of print]

tp53-dependent and independent signaling underlies the pathogenesis and possible prevention of Acrofacial Dysostosis - Cincinnati type.

Author information

1
Stowers Institute for Medical Research, Kansas City, MO, 64110 USA.
2
Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS, 66160 USA.
3
Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, Los Angeles, CA, 90033 USA.
4
Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033 USA.

Abstract

Ribosome biogenesis is a global process required for growth and proliferation in all cells, but disruptions in this process surprisingly lead to tissue-specific phenotypic disorders termed ribosomopathies. Pathogenic variants in the RNA Polymerase (Pol) I subunit POLR1A cause Acrofacial Dysostosis - Cincinnati type, which is characterized by craniofacial and limb anomalies. In a zebrafish model of Acrofacial Dysostosis - Cincinnati type, we demonstrate that polr1a-/- mutants exhibit deficient 47S rRNA transcription, reduced monosomes and polysomes and, consequently, defects in protein translation. This results in Tp53-dependent neuroepithelial apoptosis, diminished neural crest cell proliferation and cranioskeletal anomalies. This indicates that POLR1A is critical for rRNA transcription, which is considered a rate limiting step in ribosome biogenesis, underpinning its requirement for neuroepithelial cell and neural crest cell proliferation and survival. To understand the contribution of the Tp53 pathway to the pathogenesis of Acrofacial Dysostosis - Cincinnati type, we genetically inhibited tp53 in polr1a-/- mutant embryos. Tp53 inhibition suppresses neuroepithelial apoptosis and partially ameliorates the polr1a mutant phenotype. However, complete rescue of cartilage development is not observed due to the failure to improve rDNA transcription and neural crest cell proliferation. Altogether, these data reveal specific functions for both Tp53-dependent and independent signaling downstream of polr1a in ribosome biogenesis during neural crest cell and craniofacial development, in the pathogenesis of Acrofacial Dysostosis - Cincinnati type. Furthermore, our work sets the stage for identifying Tp53-independent therapies to potentially prevent Acrofacial dysostosis - Cincinnati type and other similar ribosomopathies.

PMID:
29750247
DOI:
10.1093/hmg/ddy172

Supplemental Content

Full text links

Icon for Silverchair Information Systems
Loading ...
Support Center