Analyse der molekularen und genetischen Regulation der Knochenstruktur durch Arginin Methylierung.
Evolutionäre Zell- und Entwicklungsbiologie der Tiere
Public Health, Gesundheitsbezogene Versorgungsforschung, Sozial- und Arbeitsmedizin
Zusammenfassung der Projektergebnisse
Osteoporosis is a systemic disorder, which is very common in the general world population and even more in the aging population. It is characterized by loss in bone mass and disruption of the microarchitectural structure of bone tissue, which results in loss of mechanical strength and increases risk of fracture. Understanding the pathogenic mechanisms leading to the disruption of bone mass is therefore crucial for the development of effective pharmacological treatments for osteoporosis (OP). Posttranslational modifications of intracellular and extracellular protein matrix play a major role in determining the osteoblast functions, as has been shown by recent studies in both humans and animal models. One of these mechanisms is the covalent methylation of nitrogen atoms of arginine residues by the action of protein arginine methyltransferases (PRMT). Arginine methylation plays important roles in multiple cellular processes, including inter cell communications using nitric oxide (NO), RNA processing, transcriptional regulation, signal transduction, and protein-protein interactions. As arginine methylation consequences in bone remodelling and in osteoporosis remain to be elucidated, the goal of my project was to analyse if arginine methylation could regulate critical intracellular pathways in the osteoblasts that regulate bone physiology. Unfortunately, for reasons not depending on my will, I could not proceed to perform most experiment and I could not confirm or refute my original hypothesis about the role of Prmt1 in osteoblast survival. I did get involved in the analysis of another member of the Prmt family, Prmt7. This gene has been found to be associated to a new syndrome in a new study called Deciphering Developmental Disorders (DDD) project. This project aims to analyse the genome of patients affected by delay in their physical or mental development or multiple malformations and associate the genomic mutations to a specific phenotype. A database collecting these data will allow researchers to link particular phenotypes to genetic variants, making possible in the identification of molecular targets for new treatments for some of these conditions. The syndrome associated to loss of function of Prmt7 is phenocopy of Pseudohypoparathyroidism, also known as Albright Hereditary Osteodystrophy (AHO). Characteristics included mild intellectual disability, obesity and symmetrical shortening of the digits and posterior metacarpals and metatarsals. I analysed a mouse model for a non-functional allele of Prmt7 (Prmt7tm1a/tm1a). I could confirm that Prmt7tm1a/tm1a mice displayed a similar phenotype as the human patients, with a decreased body weight and length shortly after birth. Generally Prmt7tm1a/tm1a skeletal elements were shorter compared to wt but in addition Prmt7tm1a/tm1a mice showed brachydactily of the fifth metatarsal. Also similar to the human patients, deformities of the skull were also present, the nasal bridge being significantly shortened. Endochondral ossification is the process by which most bone of the skeleton in mammals develop. It is characterized by the generation of a cartilage middlestage template between the mesenchymal condensation and the stage of ossification. The persistence of a small portion of chondrocytes (the “so-called” growth plate) at the distal end of the long bones until the end of puberty in humans, allows the longitudinal growth of the skeletal elements. Sections of the growth plate revealed that chondrocyte differentiation and maybe proliferation could be impaired in Prmt7tm1a/tm1a mice. The exact reason underlying this mild dwarfism and cartilage defects needs to be further investigated. More analysis are necessary at different and especially earlier stages of development in order to elucidate the role of Prmt7 during skeleton development and chondrocyte differentiation. In conclusion, the Prmt7tm1a/tm1a mouse resembles the human phenotype and can be a valuable model to study the development of this disease. Analysis of the cognitive abilities of this mutant could also help to understand the neuronal development pathways that are regulated by Prmt7.
Projektbezogene Publikationen (Auswahl)
- Discovery of four novel recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families. Nature Genetics volume 47, pages 1363–1369 (2015)
Akawi N, McRae J, Ansari M, Balasubramanian M, Blyth M, Brady AF, Clayton S, Cole T, Deshpande C, Fitzgerald TW, Foulds N, Francis R, Gabriel G, Gerety SS, Goodship J, Hobson E, Jones WD, Joss S, King D, Klena N, Kumar A, Lees M, Lelliott C, Lord J, McMul
(Siehe online unter https://doi.org/10.1038/ng.3410)
