Abstract
Whereas Jagged1-Notch2 signaling is known to pattern the sensorineural components of the inner ear, its role in middle ear development has been less clear. We previously reported a role for Jagged-Notch signaling in shaping skeletal elements derived from the first two pharyngeal arches of zebrafish. Here we show a conserved requirement for Jagged1-Notch2 signaling in patterning the stapes and incus middle ear bones derived from the equivalent pharyngeal arches of mammals. Mice lacking Jagged1 or Notch2 in neural crest-derived cells (NCCs) of the pharyngeal arches display a malformed stapes. Heterozygous Jagged1 knockout mice, a model for Alagille Syndrome (AGS), also display stapes and incus defects. We find that Jagged1-Notch2 signaling functions early to pattern the stapes cartilage template, with stapes malformations correlating with hearing loss across all frequencies. We observe similar stapes defects and hearing loss in one patient with heterozygous JAGGED1 loss, and a diversity of conductive and sensorineural hearing loss in nearly half of AGS patients, many of which carry JAGGED1 mutations. Our findings reveal deep conservation of Jagged1-Notch2 signaling in patterning the pharyngeal arches from fish to mouse to man, despite the very different functions of their skeletal derivatives in jaw support and sound transduction.
Highlights
Despite their critical importance in sound transduction, we still know relatively little about the developmental patterning of the diminutive ossicles of the mammalian middle ear
We had previously reported that conditional deletion of Jag[1] in neural crest-derived cells (NCCs) resulted in a persistent foramen in the frontal bone[18], and an independent group reported midfacial hypoplasia in these Wnt1-Cre; Jag1f/f conditional knockout (Jag1-CKO) mice, reminiscent of the facial characteristics of AGS19, 20
Whereas the stapes of Jag1-CKO mice were consistently reduced in size, there was some variability in the amount of ectopic mineralization in the reduced foramen (Fig. S1)
Summary
Despite their critical importance in sound transduction, we still know relatively little about the developmental patterning of the diminutive ossicles of the mammalian middle ear. Jagged-Notch signaling in the patterning of the prosensory domain, which gives rise to the hair and support cells of the cochlea[10,11,12] These findings would appear to suggest that hearing loss in AGS is primarily due to sensorineural defects. In a separate post-mortem analysis of the temporal bone, two AGS individuals were described as having a “bulky” stapes, with one displaying a “bulky” incus, yet the precise morphological changes of these middle ear bones were unclear[15] These studies raise the possibility that defects in the neural components of the inner ear and the structural components of the middle ear might contribute to hearing loss in AGS patients
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