Rigueur Diana, Roberts Ryan R, Bobzin Lauren, Merrill Amy E
Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, Los Angeles, California.
Department of Biochemistry and Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.
Genesis. 2019 Jan;57(1):e23252. doi: 10.1002/dvg.23252. Epub 2018 Oct 4.
The skeletal structure of the mammalian middle ear, which is composed of three endochondral ossicles suspended within a membranous air-filled capsule, plays a critical role in conducting sound. Gene mutations that alter skeletal development in the middle ear result in auditory impairment. Mutations in fibroblast growth factor receptor 2 (FGFR2), an important regulator of endochondral and intramembranous bone formation, cause a spectrum of congenital skeletal disorders featuring conductive hearing loss. Although the middle ear malformations in multiple FGFR2 gain-of-function disorders are clinically characterized, those in the FGFR2 loss-of-function disorder lacrimo-auriculo-dento-digital (LADD) syndrome are relatively undescribed. To better understand conductive hearing loss in LADD, we examined the middle ear skeleton of mice with conditional loss of Fgfr2. We find that decreased auditory function in Fgfr2 mutant mice correlates with hypoplasia of the auditory bulla and ectopic bone growth at sites of tendon/ligament attachment. We show that ectopic bone associated with the intra-articular ligaments of the incudomalleal joint is derived from Scx-expressing cells and preceded by decreased expression of the joint progenitor marker Gdf5. Together, these results identify a role for Fgfr2 in development of the middle ear skeletal tissues and suggest potential causes for conductive hearing loss in LADD syndrome.
哺乳动物中耳的骨骼结构由悬浮在充满空气的膜性囊内的三块软骨内小骨组成，在声音传导中起关键作用。改变中耳骨骼发育的基因突变会导致听力障碍。成纤维细胞生长因子受体2（FGFR2）是软骨内和膜内骨形成的重要调节因子，其突变会导致一系列以传导性听力损失为特征的先天性骨骼疾病。尽管多种FGFR2功能获得性疾病中的中耳畸形有临床特征描述，但FGFR2功能丧失性疾病泪腺-耳-牙-指（LADD）综合征中的中耳畸形相对较少被描述。为了更好地理解LADD中的传导性听力损失，我们检查了条件性Fgfr2缺失小鼠的中耳骨骼。我们发现Fgfr2突变小鼠的听觉功能下降与听泡发育不全以及肌腱/韧带附着部位的异位骨生长有关。我们表明，与砧镫关节关节内韧带相关的异位骨源自表达Scx的细胞，并且在关节祖细胞标志物Gdf5表达降低之前出现。这些结果共同确定了Fgfr在中耳骨骼组织发育中的作用，并提示了LADD综合征中传导性听力损失的潜在原因。
