Prevention of guanylyl cyclase-B dephosphorylation rescues achondroplastic dwarfism.

Abstract

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 2 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 2-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 WT versions of both receptors. We conclude that preventing GC-B dephosphorylation rescues reduced axial and appendicular skeleton growth in a mouse model of achondroplasia.

• Authors: Brandon M Wagner, Jerid W Robinson, Yun-Wen Lin, Yi-Ching Lee, Nabil Kaci, Laurence Legeai-Mallet, Lincoln R Potter
• Journal: JCI insight (JCI Insight) Vol. 6 Issue 9 (05 10 2021) ISSN: 2379-3708 [Electronic] United States
• PMID: 33784257 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Fgfr3 protein, mouse
• Receptor, Fibroblast Growth Factor, Type 3
• Receptors, Atrial Natriuretic Factor
• atrial natriuretic factor receptor B

Topics

• Achondroplasia (genetics)
• Animals
• Body Size (genetics)
• Bone Development (genetics)
• Femur (growth & development)
• Growth Plate (growth & development, pathology)
• Mice
• Mice, Transgenic
• Organ Size
• Phosphorylation
• Receptor, Fibroblast Growth Factor, Type 3 (genetics)
• Receptors, Atrial Natriuretic Factor (genetics, metabolism)
• Skull (growth & development)
• Tibia (growth & development)