Limb specific Acvr1-knockout during embryogenesis in mice exhibits great toe malformation as seen in Fibrodysplasia Ossificans Progressiva (FOP)
| Autor: | Laura de Campos Hildebrand, Katja Stange, Mareen Schmidt-von Kegler, Maria Walther, Petra Seemann |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Mesoderm Embryonic Development In situ hybridization Biology ACVR1 03 medical and health sciences Mice 0302 clinical medicine Conditional gene knockout medicine Animals Humans FOP Mice Knockout Cartilage Embryogenesis Extremities Toes medicine.disease Embryo Mammalian Patterns & Phenotypes Phenotype Cell biology skeletal malformation 030104 developmental biology medicine.anatomical_structure Myositis Ossificans Fibrodysplasia ossificans progressiva Bone Morphogenetic Proteins Acvr1 cKO Activin Receptors Type I 030217 neurology & neurosurgery Developmental Biology Signal Transduction |
| Zdroj: | Developmental Dynamics |
| ISSN: | 1097-0177 |
| Popis: | Purpose This study analyzes Prx1‐specific conditional knockout of Acvr1 aiming to elucidate the endogenous role of Acvr1 during limb formation in early embryonic development. ACVR1 can exhibit activating and inhibiting function in BMP signaling. ACVR1 gain‐of‐function mutations can cause the rare disease fibrodysplasia ossificans progressiva (FOP), where patients develop ectopic bone replacing soft tissue, tendons and ligaments. Methods Whole‐mount in situ hybridization and skeletal preparations revealed that following limb‐specific conditional knockout of Acvr1, metacarpals and proximal phalanges were shortened and additional cartilage and bone elements were formed. Results The analysis of a set of marker genes including ligands and receptors of BMP signaling as well as genes involved in patterning and tendon and cartilage formation, revealed temporal disturbances with distinct spatial patterns. The most striking result was that in the absence of Acvr1 in mesoderm precursor cells, first digits were drastically malformed. Conclusion In FOP, malformation of big toes can serve as a first soft marker in diagnostics. The surprising similarities in phenotype between the described conditional knockout of Acvr1 and the FOP mouse model, indicates a natural inhibitory function of ACVR1. This represents a further step towards better understanding the role of Acvr1 and developing treatment options for FOP. Key Findings Limb specific conditional KO of Acvr1 leads to shortened extremities and to heterotopic cartilage and bone formation.Acvr1 is particularly involved in the development of the first digit.Phenotypic similarities between the limb specific cKO of Acvr1 and the FOP mouse model, carrying the gain of function mutation p.R206H in Acvr1, indicates a natural inhibitory function of Acvr1. |
| Databáze: | OpenAIRE |
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