Over Half the Hair Cells in the Mouse Utricle First Appear After Birth, with Significant Numbers Originating from Early Postnatal Mitotic Production in Peripheral and Striolar Growth Zones

Abstract

Many non-mammalian vertebrates produce hair cells throughout life and recover from hearing and balance deficits through regeneration. In contrast, embryonic production of hair cells declines sharply in mammals where deficits from hair cell losses are typically permanent. Hair cell density estimates recently suggested that the vestibular organs of mice continue to add hair cells after birth, so we undertook comprehensive counting in murine utricles at different ages. The counts show that 51 % of the hair cells in adults arise during the 2 weeks after birth. Immature hair cells are most common near the neonatal macula's peripheral edge and striola, where anti-Ki-67 labels cycling nuclei in zones that appear to contain niches for supporting-cell-like stem cells. In vivo lineage tracing in a novel reporter mouse where tamoxifen-inducible supporting cell-specific Cre expression switched tdTomato fluorescence to eGFP fluorescence showed that proteolipid-protein-1-expressing supporting cells are an important source of the new hair cells. To assess the contributions of postnatal cell divisions, we gave mice an injection of BrdU or EdU on the day of birth. The labels were restricted to supporting cells 1 day later, but by 12 days, 31 % of the labeled nuclei were in myosin-VIIA-positive hair cells. Thus, hair cell populations in neonatal mouse utricles grow appreciably through two processes: the progressive differentiation of cells generated before birth and the differentiation of new cells arising from divisions of progenitors that progress through S phase soon after birth. Subsequent declines in these processes coincide with maturational changes that appear unique to mammalian supporting cells.

SoxC transcription factors are essential for the development of the inner ear

“…By culturing the organs in medium supplemented with 5-ethynyl-2′-deoxyuridine (EdU), we labeled the proliferating cells at each stage. In accord with previous results (14), we observed proliferating cells at the periphery of the utricular macula and in the striola, the organ's central region (Fig. S1 A-C).…”

“…To ascertain whether the morphological abnormalities of the vestibular organs in the SoxC CKO mice arose from deficiencies in supporting cell proliferation, we labeled proliferating cells with EdU and analyzed the inner ears of E18.5 embryos. As shown previously (14), a band of proliferating supporting cells occurred along the convex abneural periphery of a WT utricle (Fig. 4E).…”

“…Reasoning that this transition should be reflected by differences in the expression of genes involved in proliferation, differentiation, and regeneration, we investigated the genes expressed late in the development of the murine utricle. With a simple architecture and just under 4,000 hair cells in an adult animal (14), the sensory epithelium of the utricle-the macularepresents a useful model system. Although gene expression has been characterized in early otic development (15,16) and in the neonatal organ of Corti (17,18), corresponding data are lacking for the developing utricle.…”

Expression Profiling of MicroRNAs in the Inner Ear of Elderly People by Real-Time PCR Quantification

“…Notably, hair cells of the adult cochlea in mammals do not usually regenerate. Vestibular hair cells have been known to regenerate when injured [Warchol et al, 1993;Yamane et al, 1995], and others have found that half of the hair cells in the mouse utricle first appear after birth, but that they only appear 2 weeks after birth [Burns et al, 2012]. However, regeneration of inner ear cells is not typical.…”

Segregating neural and mechanosensory fates in the developing ear: patterning, signaling, and transcriptional control

“…Neurogenesis and the production of sensory patches continue together for several days until neurogenesis is extinguished (Raft, et al, 2007). However, sensory tissue continues to differentiate for days and sometimes weeks: for instance, the mouse utricular macula does not finish adding hair cells until two weeks after birth (Burns, et al, 2012). …”