An Essential Requirement for Fgf10 in Pinna Extension Sheds Light on Auricle Defects in LADD Syndrome

Abstract

The pinna (or auricle) is part of the external ear, acting to capture and funnel sound toward the middle ear. The pinna is defective in a number of craniofacial syndromes, including Lacrimo-auriculo-dento-digital (LADD) syndrome, which is caused by mutations in FGF10 or its receptor FGFR2b. Here we study pinna defects in the Fgf10 knockout mouse. We show that Fgf10 is expressed in both the muscles and forming cartilage of the developing external ear, with loss of signaling leading to a failure in the normal extension of the pinna over the ear canal. Conditional knockout of Fgf10 in the neural crest fails to recapitulate this phenotype, suggesting that the defect is due to loss of Fgf10 from the muscles, or that this source of Fgf10 can compensate for loss in the forming cartilage. The defect in the Fgf10 null mouse is driven by a reduction in proliferation, rather than an increase in cell death, which can be partially phenocopied by inhibiting cell proliferation in explant culture. Overall, we highlight the mechanisms that could lead to the phenotype observed in LADD syndrome patients and potentially explain the formation of similar low-set and cup shaped ears observed in other syndromes.

Validation of a Novel Fgf10Cre–ERT2 Knock-in Mouse Line Targeting FGF10Pos Cells Postnatally

“…Additionally, tamoxifen treatment at E15.5 revealed strong fluorescent signal in the pinna of the developing ear as well as in the trachea and in between the cartilage rings (Figure 4C). These two additional expression domains are consistent with sites of Fgf10 expression (Sala et al, 2011;Zhang et al, 2020). We therefore conclude that Cre expression reflects Fgf10 expression and that this line can be used to target FGF10 Pos cells.…”

Identification of Hub Genes in Hemifacial Microsomia: Evidence From Bioinformatic Analysis

“…12 Conditional knockout of Fgf10 in mice was not succeed in recurrencing ear anomalies phenotypes, suggesting that ear deformities is due to network compensatory regulation when single gene deletion. 13 FGFR1 played an important role for localized signaling in the pharyngeal ectoderm and major in the embryological second branchial arch development.…”

“…Both mandible and forming cartilage of the development of pinna require enough expression of FGF10, with loss of signaling failing to normal formation of auricle extension and mandible 12 . Conditional knockout of Fgf10 in mice was not succeed in recurrencing ear anomalies phenotypes, suggesting that ear deformities is due to network compensatory regulation when single gene deletion 13 …”

Dysregulation in Spatiotemporal Expression ofHMX1Coordinated by Multifaceted Enhancers Drives an Auricular Disorder

“…The outer ear, essential for capturing sound waves and implicated in conductive hearing loss when dysfunctional, is less explored than its middle and inner counterparts 3 . This part, comprising the tragus and helix, is not only important for auditory function but also demonstrates considerable morphological diversity throughout evolution as well as in many types of diseases [4][5][6][7] . Unraveling the molecular mechanisms underlying this diversity is an ongoing field of investigation.…”