ErbB Expression: The Mouse Inner Ear and Maturation of the Mitogenic Response to Heregulin

Abstract

In humans, hair cell loss often leads to hearing and balance impairments. Hair cell replacement is vigorous and spontaneous in avians and nonmammalian vertebrates. In mammals, in contrast, it occurs at a very low rate, or not at all, presumably because of a very low level of supporting cell proliferation following injury. Heregulin (HRG), a member of the epidermal growth factor (EGF) family of growth factors, is reported to be a potent mitogen for neonatal rat vestibular sensory epithelium, but its effects in adults are unknown. We report here that HRG-a stimulates cell proliferation in organotypic cultures of neonatal, but not adult, mouse utricular sensory epithelia. Our findings support the idea that the proliferative capabilities of the adult mammalian vestibular sensory epithelia differ significantly from that seen in neonatal animals. Immunohistochemistry reveals that HRG-binding receptors (erbBs 2-4) and erbB1 are widely expressed in vestibular and auditory sensory epithelia in neonatal and adult mouse inner ear. The distribution of erbBs in the neonatal and adult mouse ear is consistent with the EGF receptor/ligand family regulating diverse cellular processes in the inner ear, including cell proliferation and differentiation.

Survival of Adult Spiral Ganglion Neurons Requires erbB Receptor Signaling in the Inner Ear

“…Specifically, because the DN-erbB4 probe that we used is almost identical to the murine erbB4, the absence of hybridization in the wild-type cochlear tissue also indicates that erbB4 is not expressed in the wild-type cochlea. These results differ somewhat from those of a study reporting that supporting cells in the adult cochlea express erbB2, erbB3, and erbB4, whereas hair cells express erbB2 and erbB3 (Hume et al, 2003). The differences may be attributable to the different ages analyzed: P15 in the present study versus 4 -12 weeks in the Hume et al (2003) study.…”

“…These results differ somewhat from those of a study reporting that supporting cells in the adult cochlea express erbB2, erbB3, and erbB4, whereas hair cells express erbB2 and erbB3 (Hume et al, 2003). The differences may be attributable to the different ages analyzed: P15 in the present study versus 4 -12 weeks in the Hume et al (2003) study. Nevertheless, the specific expression of DN-erbB4 in supporting cells in our transgenic line shows that erbB receptors expressed by supporting cells are critical for the function of the adult cochlea.…”

Evaluation of Lapatinib and Trastuzumab for Ototoxic Effects

“…In the literature, erlotinib and imatinib dependent ototoxicity have been reported, as they are tyrosine kinase inhibitors that effect ototoxicity along a different pathway [1,6,9] . When we examine the studies relating tyrosine kinase inhibitors to hearing loss, many of them displayed mechanisms related to EGFR and HER [10,11] . EGF-1 and HER2,3,4 receptors were found in the rat inner ear [10] .…”

“…When we examine the studies relating tyrosine kinase inhibitors to hearing loss, many of them displayed mechanisms related to EGFR and HER [10,11] . EGF-1 and HER2,3,4 receptors were found in the rat inner ear [10] . Also, EGFR has been found to be important in cell growth of the cochlea in rats [11] .…”

Has hair cell loss MET its match?

“…Finally, it is important to consider that it is not known whether a similar approach will work with mammalian cells. As the authors suggest, there is no reason to think that a forced MET will be less effective at inducing formation of hair cell-containing spheres from mammalian tissue, but considering the relatively limited innate proliferative potential of mammalian supporting cells, expansion of these cells while in a mesenchymal form may prove more challenging (18)(19)(20)(21)(22)(23).…”