Prevention of guanylyl cyclase–B dephosphorylation rescues achondroplastic dwarfism
| Autor: | Yun Wen Lin, Brandon M. Wagner, Laurence Legeai-Mallet, Jerid W. Robinson, Lincoln R. Potter, Nabil Kaci, Yi Ching Lee |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Long bone Dwarfism Mice Transgenic Biology Achondroplasia Dephosphorylation Mice 03 medical and health sciences Bone biology 0302 clinical medicine Bone disease Internal medicine medicine Animals Body Size Receptor Fibroblast Growth Factor Type 3 Femur Growth Plate Phosphorylation Receptor Bone Development Tibia Skull Wild type Organ Size General Medicine Fibroblast growth factor receptor 3 Guanylate cyclase medicine.disease NPR2 030104 developmental biology medicine.anatomical_structure Endocrinology 030220 oncology & carcinogenesis Medicine Receptors Atrial Natriuretic Factor Research Article |
| Zdroj: | JCI Insight, Vol 6, Iss 9 (2021) JCI Insight |
| ISSN: | 2379-3708 |
| Popis: | Activating mutations in the fibroblast growth factor receptor 3 (FGFR3) or inactivating mutations in guanylyl cyclase B (GC-B), also known as NPR-B or Npr2, cause short-limbed dwarfism. FGFR3 activation causes dephosphorylation and inactivation of GC-B, but the contribution of GC-B dephosphorylation to achondroplasia (ACH) is unknown. GC-B7E/7E mice that express a glutamate-substituted version of GC-B that cannot be inactivated by dephosphorylation were bred with mice expressing FGFR3-G380R, the most common human ACH mutation, to determine if GC-B dephosphorylation is required for ACH. Crossing GC-B7E/7E mice with FGFR3G380R/G380R mice increased naso-anal and long (tibia and femur), but not cranial, bone length twice as much as crossing GC-B7E/7E mice with FGFR3WT/WT mice from 4 to 16 weeks of age. Consistent with increased GC-B activity rescuing ACH, long bones from the GC-B7E/7E/FGFR3G380R/G380R mice were not shorter than those from GC-BWT/WT/FGFR3WT/WT mice. At two weeks of age, male but not female FGFR3G380R/G380R mice had shorter long bones and smaller growth plate hypertrophic zones, whereas female but not male GC-B7E/7E mice had longer bones and larger hypertrophic zones. In two-week old males, crossing FGFR3G380R/G380R mice with GC-B7E/7E mice increased long bone length and hypertrophic zone area to levels observed in mice expressing wild type versions of both receptors. We conclude that preventing GC-B dephosphorylation rescues reduced axial and appendicular skeleton growth in a mouse model of achondroplasia. |
| Databáze: | OpenAIRE |
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