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FGFR3 overactivation in the brain is responsible for memory impairments in Crouzon syndrome mouse model.
- Source :
-
The Journal of experimental medicine [J Exp Med] 2022 Apr 04; Vol. 219 (4). Date of Electronic Publication: 2022 Mar 07. - Publication Year :
- 2022
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Abstract
- Crouzon syndrome with acanthosis nigricans (CAN, a rare type of craniosynostosis characterized by premature suture fusion and neurological impairments) has been linked to a gain-of-function mutation (p.Ala391Glu) in fibroblast growth factor receptor 3 (FGFR3). To characterize the CAN mutation's impact on the skull and on brain functions, we developed the first mouse model (Fgfr3A385E/+) of this syndrome. Surprisingly, Fgfr3A385E/+ mice did not exhibit craniosynostosis but did show severe memory impairments, a structurally abnormal hippocampus, low activity-dependent synaptic plasticity, and overactivation of MAPK/ERK and Akt signaling pathways in the hippocampus. Systemic or brain-specific pharmacological inhibition of FGFR3 overactivation by BGJ398 injections rescued the memory impairments observed in Fgfr3A385E/+ mice. The present study is the first to have demonstrated cognitive impairments associated with brain FGFR3 overactivation, independently of skull abnormalities. Our results provide a better understanding of FGFR3's functional role and the impact of its gain-of-function mutation on brain functions. The modulation of FGFR3 signaling might be of value for treating the neurological disorders associated with craniosynostosis.<br />Competing Interests: Disclosures: L. Legeai-Mallet and F. Oury reported a patent to BIO19248 pending. No other disclosures were reported.<br /> (© 2022 Cornille et al.)
Details
- Language :
- English
- ISSN :
- 1540-9538
- Volume :
- 219
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- The Journal of experimental medicine
- Publication Type :
- Academic Journal
- Accession number :
- 35254402
- Full Text :
- https://doi.org/10.1084/jem.20201879