1. Cytoplasmic polyadenylation by TENT5A is required for proper bone formation
- Author
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Aleksander Chlebowski, Goretti Aranaz-Novaliches, Olga Kofroňová, Oldrich Benada, Andrzej Dziembowski, Monika Kusio-Kobiałka, Dominik Cysewski, Radislav Sedlacek, Jan Prochazka, Bartosz Tarkowski, Olga Gewartowska, Pawel S. Krawczyk, Marcin Szpila, Piotr Szwedziak, Frantisek Spoutil, Jakub Gruchota, and Seweryn Mroczek
- Subjects
0301 basic medicine ,Male ,Bone disease ,Polyadenylation ,osteogenesis imperfecta ,Matrix (biology) ,Mice ,0302 clinical medicine ,Protein Isoforms ,Osteonectin ,polyadenylation ,Biology (General) ,Polymerase ,Mice, Knockout ,biology ,Chemistry ,Gene Expression Regulation, Developmental ,Polynucleotide Adenylyltransferase ,osteoblasts ,Osteoblast ,Cell Differentiation ,Nucleotidyltransferases ,Cell biology ,medicine.anatomical_structure ,TENT5A ,Osteogenesis imperfecta ,Female ,Type I collagen ,Signal Transduction ,QH301-705.5 ,General Biochemistry, Genetics and Molecular Biology ,Collagen Type I ,osteogenesis ,03 medical and health sciences ,Calcification, Physiologic ,FAM46A ,medicine ,Animals ,Humans ,Secretion ,Nerve Growth Factors ,RNA, Messenger ,Eye Proteins ,Serpins ,Sequence Analysis, RNA ,RNA ,medicine.disease ,Collagen Type I, alpha 1 Chain ,Disease Models, Animal ,030104 developmental biology ,Cytoplasm ,biology.protein ,030217 neurology & neurosurgery - Abstract
Summary: Osteoblasts orchestrate bone formation through the secretion of type I collagen and other constituents of the matrix on which hydroxyapatite crystals mineralize. Here, we show that TENT5A, whose mutations were found in congenital bone disease osteogenesis imperfecta patients, is a cytoplasmic poly(A) polymerase playing a crucial role in regulating bone mineralization. Direct RNA sequencing revealed that TENT5A is induced during osteoblast differentiation and polyadenylates mRNAs encoding Col1α1, Col1α2, and other secreted proteins involved in osteogenesis, increasing their expression. We postulate that TENT5A, possibly together with its paralog TENT5C, is responsible for the wave of cytoplasmic polyadenylation of mRNAs encoding secreted proteins occurring during bone mineralization. Importantly, the Tent5a knockout (KO) mouse line displays bone fragility and skeletal hypomineralization phenotype resulting from quantitative and qualitative collagen defects. Thus, we report a biologically relevant posttranscriptional regulator of collagen production and, more generally, bone formation.
- Published
- 2021