Prevention of guanylyl cyclase–B dephosphorylation rescues achondroplastic dwarfism

Brandon M Wagner, Jerid W Robinson, Yun Wen Lin, Yi Ching Lee, Nabil Kaci, Laurence Legeai-Mallet, Lincoln R. Potter

Research output: Contribution to journalArticlepeer-review

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 GCB7E/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.

Original languageEnglish (US)
Article numbere147832
JournalJCI Insight
Volume6
Issue number9
DOIs
StatePublished - May 10 2021

Bibliographical note

Funding Information:
The authors wish to thank Laurinda Jaffe, Leia Shuhaibar, and Siu-Pok Yee for many helpful conversations and instructive comments regarding this manuscript. We are grateful to Ruey-Bing Yang for bringing the Potter and Lee laboratories together for this project. We thank Snigdhansu Chatterjee of the University of Minnesota School of Statistics for advice regarding the statistical comparisons of naso-anal lengths between various mouse lines. This work was supported by NIH grants R01GM098309 and NIHT32DK007203, a University of Minnesota Foundation Bridge Grant, a University of Minnesota-Mayo Clinic Partnership grant, a University of Minnesota Academic Health Center Faculty Research and Development grant, and grants from the Fund for Science and the Hormone Receptor Fund to LRP. LLM received a state subsidy managed by the National Research Agency under the ?Investments for the Future? program (ANR-10-IAHU-01) that funded a portion of the work described in this manuscript.

Funding Information:
The authors wish to thank Laurinda Jaffe, Leia Shuhaibar, and Siu-Pok Yee for many helpful conversations and instructive comments regarding this manuscript. We are grateful to Ruey-Bing Yang for bringing the Potter and Lee laboratories together for this project. We thank Snigdhansu Chatterjee of the University of Minnesota School of Statistics for advice regarding the statistical comparisons of naso-anal lengths between various mouse lines. This work was supported by NIH grants R01GM098309 and NIHT32DK007203, a University of Minnesota Foundation Bridge Grant, a University of Minnesota-Mayo Clinic Partnership grant, a University of Minnesota Academic Health Center Faculty Research and Development grant, and grants from the Fund for Science and the Hormone Receptor Fund to LRP. LLM received a state subsidy managed by the National Research Agency under the “Investments for the Future” program (ANR-10-IA-HU-01) that funded a portion of the work described in this manuscript.

Publisher Copyright:
© 2021, Wagner et al.

PubMed: MeSH publication types

  • Journal Article

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