The Notch Ligand JAG1 Is Required for Sensory Progenitor Development in the Mammalian Inner Ear

Harvard Medical School, United States of America
PLoS Genetics (Impact Factor: 7.53). 02/2006; 2(1):e4. DOI: 10.1371/journal.pgen.0020004
Source: PubMed


In mammals, six separate sensory regions in the inner ear are essential for hearing and balance function. Each sensory region is made up of hair cells, which are the sensory cells, and their associated supporting cells, both arising from a common progenitor. Little is known about the molecular mechanisms that govern the development of these sensory organs. Notch signaling plays a pivotal role in the differentiation of hair cells and supporting cells by mediating lateral inhibition via the ligands Delta-like 1 and Jagged (JAG) 2. However, another Notch ligand, JAG1, is expressed early in the sensory patches prior to cell differentiation, indicating that there may be an earlier role for Notch signaling in sensory development in the ear. Here, using conditional gene targeting, we show that the Jag1 gene is required for the normal development of all six sensory organs within the inner ear. Cristae are completely lacking in Jag1-conditional knockout (cko) mutant inner ears, whereas the cochlea and utricle show partial sensory development. The saccular macula is present but malformed. Using SOX2 and p27kip1 as molecular markers of the prosensory domain, we show that JAG1 is initially expressed in all the prosensory regions of the ear, but becomes down-regulated in the nascent organ of Corti by embryonic day 14.5, when the cells exit the cell cycle and differentiate. We also show that both SOX2 and p27kip1 are down-regulated in Jag1-cko inner ears. Taken together, these data demonstrate that JAG1 is expressed early in the prosensory domains of both the cochlear and vestibular regions, and is required to maintain the normal expression levels of both SOX2 and p27kip1. These data demonstrate that JAG1-mediated Notch signaling is essential during early development for establishing the prosensory regions of the inner ear.

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Available from: Amy Kiernan, Aug 26, 2015
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    • "During early development, Notch induces prosensory domains through lateral induction, but inhibits hair cell formation later in development through lateral inhibition (Kiernan, 2013; Neves et al., 2013). Mouse mutants in the Notch ligand Jagged1 show a reduction in the size of the prosensory domain, and overall fewer hair cells (Kiernan et al., 2006; Brooker et al., 2006). In agreement with the Jagged1 results, early overexpression of an activated form of Notch, NICD, is sufficient to induce ectopic prosensory regions containing hair cells and support cells in mouse and chicken (Hartman et al., 2010; Pan et al., 2010; Daudet and Lewis, 2005). "
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    ABSTRACT: Background: Damage or destruction of sensory hair cells in the inner ear leads to hearing or balance deficits that can be debilitating, especially in older adults. Unfortunately, the damage is permanent, as regeneration of the inner ear sensory epithelia does not occur in mammals. Results: Zebrafish and other non-mammalian vertebrates have the remarkable ability to regenerate sensory hair cells and understanding the molecular and cellular basis for this regenerative ability will hopefully aid us in designing therapies to induce regeneration in mammals. Zebrafish not only possess hair cells in the ear but also in the sensory lateral line system. Hair cells in both organs are functionally analogous to hair cells in the inner ear of mammals. The lateral line is a mechanosensory system found in most aquatic vertebrates that detects water motion and aids in predator avoidance, prey capture, schooling, and mating. Although hair cell regeneration occurs in both the ear and lateral line, most research to date has focused on the lateral line due to its relatively simple structure and accessibility. Conclusions: Here we review the recent discoveries made during the characterization of hair cell regeneration in zebrafish.
    Developmental Dynamics 10/2014; 243(10). DOI:10.1002/dvdy.24167 · 2.38 Impact Factor
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    • "These two modes of operation rely, in each case, on the associated gene regulatory circuit. The prosensory function of Notch is mediated by the Notch ligand jagged 1 [Jag1; also known as serrate 1 (Ser1) in chick] (Eddison et al., 2000; Brooker et al., 2006; Kiernan et al., 2006; Daudet et al., 2007; Hartman et al., 2010; Pan et al., 2010; Neves et al., 2011). In the developing inner ear, Jag1 induces its own expression in adjacent cells and the expression of prosensory genes such as Sox2, resulting in the homogenous commitment of otic progenitors to the prosensory fate (Neves et al., 2011). "
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    ABSTRACT: During inner ear development, Notch exhibits two modes of operation: lateral induction, which is associated with prosensory specification, and lateral inhibition, which is involved in hair cell determination. These mechanisms depend respectively on two different ligands, jagged 1 (Jag1) and delta 1 (Dl1), that rely on a common signaling cascade initiated after Notch activation. In the chicken otocyst, expression of Jag1 and the Notch target Hey1 correlates well with lateral induction, whereas both Jag1 and Dl1 are expressed during lateral inhibition, as are Notch targets Hey1 and Hes5. Here, we show that Jag1 drives lower levels of Notch activity than Dl1, which results in the differential expression of Hey1 and Hes5. In addition, Jag1 interferes with the ability of Dl1 to elicit high levels of Notch activity. Modeling the sensory epithelium when the two ligands are expressed together shows that ligand regulation, differential signaling strength and ligand competition are crucial to allow the two modes of operation and for establishing the alternate pattern of hair cells and supporting cells. Jag1, while driving lateral induction on its own, facilitates patterning by lateral inhibition in the presence of Dl1. This novel behavior emerges from Jag1 acting as a competitive inhibitor of Dl1 for Notch signaling. Both modeling and experiments show that hair cell patterning is very robust. The model suggests that autoactivation of proneural factor Atoh1, upstream of Dl1, is a fundamental component for robustness. The results stress the importance of the levels of Notch signaling and ligand competition for Notch function.
    Development 05/2014; 141(11). DOI:10.1242/dev.108100 · 6.46 Impact Factor
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    • "It is also possible that after adopting the primordial HC fate in the HC lineage, the default cell fate is IHCs. This possibility is supported by the fact that in many genetic mutant mice IHCs were better maintained or their numbers were increased, although the total HC numbers were decreased [59], [60]. Moreover, IHCs are the primary mechanosensory receptors whereas OHCs are specific to mammals. "
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    ABSTRACT: Regeneration of auditory hair cells (HCs) is a promising approach to restore hearing. Recent studies have demonstrated that induced pluripotent stem cells/embryonic stem cells or supporting cells (SCs) adjacent to HCs can be converted to adopt the HC fate. However, little is known about whether new HCs are characteristic of outer or inner HCs. Here, we showed in vivo conversion of 2 subtypes of SCs, inner border cells (IBs) and inner phalangeal cells (IPhs), to the inner HC (IHC) fate. This was achieved by ectopically activating Atoh1, a transcription factor necessary for HC fate, in IBs/IPhs at birth. Atoh1+ IBs/IPhs first turned on Pou4f3, another HC transcription factor, before expressing 8 HC markers. The conversion rate gradually increased from ∼2.4% at 1 week of age to ∼17.8% in adult. Interestingly, new HCs exhibited IHC characteristics such as straight line-shaped stereociliary bundles, expression of Fgf8 and otoferlin, and presence of larger outward currents than those of outer HCs. However, new HCs lacked the terminal differentiation IHC marker vGlut3, exhibited reduced density of presynaptic Cbtp2 puncta that had little postsynaptic GluR2 specialization, and displayed immature IHC outward currents. Our results demonstrate that the conversion rate of IBs/IPhs in vivo by Atoh1 ectopic expression into the IHC fate was higher and faster and the conversion was more complete than that of the 2 other SC subtypes underneath the outer HCs; however, these new IHCs are arrested before terminal differentiation. Thus, IBs/IPhs are good candidates to regenerate IHCs in vivo.
    PLoS ONE 02/2014; 9(2):e89377. DOI:10.1371/journal.pone.0089377 · 3.23 Impact Factor
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