A Ser252Trp substitution in mouse FGFR2 results in hyperplasia of embryonic salivary gland parenchyma

Tsukasa Watanabe; Kaori Kometani-Gunjigake; Kayoko Nakao-Kuroishi; Misa Ito-Sago; Masahiro Mizuhara; Daiki Iwata; Keiji Moriyama; Kentaro Ono; Tatsuo Kawamoto

doi:10.1016/j.job.2021.02.008

A Ser252Trp substitution in mouse FGFR2 results in hyperplasia of embryonic salivary gland parenchyma

J Oral Biosci. 2021 Jun;63(2):184-191. doi: 10.1016/j.job.2021.02.008. Epub 2021 Mar 5.

Authors

Tsukasa Watanabe¹, Kaori Kometani-Gunjigake¹, Kayoko Nakao-Kuroishi¹, Misa Ito-Sago¹, Masahiro Mizuhara¹, Daiki Iwata¹, Keiji Moriyama², Kentaro Ono³, Tatsuo Kawamoto⁴

Affiliations

¹ Division of Orofacial Functions and Orthodontics, Kyushu Dental University, 2-6-1 Manazuru, Kokurakita-ku, Kitakyushu, Fukuoka, 803-8580, Japan.
² Department of Maxillofacial Orthognathics, Division of Maxillofacial and Neck Reconstruction, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
³ Division of Physiology, Kyushu Dental University, 2-6-1 Manazuru, Kokurakita-ku, Kitakyushu, Fukuoka, 803-8580, Japan.
⁴ Division of Orofacial Functions and Orthodontics, Kyushu Dental University, 2-6-1 Manazuru, Kokurakita-ku, Kitakyushu, Fukuoka, 803-8580, Japan. Electronic address: r15kawamoto@fa.kyu-dent.ac.jp.

PMID: 33684522
DOI: 10.1016/j.job.2021.02.008

Abstract

Objectives: Mutations in the fibroblast growth factor receptor 2 (FGFR2) gene are responsible for several severe forms of craniosynostotic disorders, such as Apert and Crouzon syndromes. Patients with craniosynostotic disorders caused by a mutation in Fgfr2 present with several clinical symptoms, including hypersalivation. Here we used a transgenic mouse model of Apert syndrome (Fgfr2^+/S252W mice) to evaluate the morphology of the submandibular glands at embryonic day 15.5 (E15.5), the time point reported to mark the start of lumen formation.

Methods: Fgfr2^+/S252W mice were generated by crossing ACTB-Cre^+/+ and Fgfr2^+/Neo-S252W mice. After measuring body weight, the submandibular glands were collected at E15.5. H&E staining, immunostaining, and RT-qPCR were performed to investigate the development of the submandibular gland.

Results: The number of ducts and acini in Fgfr2^+/S252W mice was significantly higher than in control littermates; however, lumen formation was not affected. The mRNA expression of Fgf1, Fgfr1, Mmp2, Bmp4, Bmp7, Dusp6, and Etv5 in Fgfr2^+/S252W mice was significantly higher compared to control littermates. Immunoreactivity for FGF3, FGF1, BMP4, and F4/80 was detected in the parenchyma of Fgfr2^+/S252W mice. The area of apoptotic cells stained with TUNEL in Fgfr2^+/S252W mice was significantly larger than that of the control littermates.

Conclusions: These results suggested that increased FGFR1 signaling and apoptosis in the submandibular glands of Fgfr2^+/S252W mice occurred at E15.5, leading to parenchymal hyperplasia. This study demonstrated that a Ser252Trp substitution in mouse FGFR2 resulted in hyperplasia of the submandibular gland parenchyma during development.

Keywords: Apert Syndrome; Embryo Development; FGF Receptors; Morphogenesis; Submandibular gland.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acrocephalosyndactylia*
Animals
Humans
Hyperplasia / genetics
Mice
Mice, Transgenic
Receptor, Fibroblast Growth Factor, Type 2* / genetics
Salivary Glands

Substances

FGFR2 protein, human
Fgfr2 protein, mouse
Receptor, Fibroblast Growth Factor, Type 2