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
    • "The Notch pathway could block proliferation by regulating the expression of cell cycle inhibitors. In the developing mouse cochlea, Notch signalling acts upstream of cell cycle inhibitor p27 KIP1 , and in the regenerating neuromasts, down-regulation of Notch signalling correlates with a decrease in the expression of cell cycle inhibitors (Brooker et al., 2006;Jiang et al., 2014;Kiernan et al., 2006;Murata et al., 2009). Thus, it is possible that in the lateral line, Notch signalling controls the proliferation of supporting cells by positively regulating the expression of genes blocking cell cycle progression. "
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    ABSTRACT: The Wnt and Notch signalling pathways control proliferation, specification, and cell fate choices during embryonic development and in adult life. Hence, there is much interest in both signalling pathways in the context of stem cell biology and tissue regeneration. In the developing ear, the Wnt and Notch signalling pathways specify otic cells and refine the ventral boundary of the otic placode. Since both signalling pathways control events essential for the formation of sensory cells, such as proliferation and hair cell differentiation, these pathways could hold promise for the regeneration of hair cells in adult mammalian cochlea. Indeed, modulating either the Wnt or Notch pathways can trigger the regenerative potential of supporting cells. In the neonatal mouse cochlea, Notch-mediated regeneration of hair cells partially depends on Wnt signalling, which implies an interaction between the pathways. This review presents how the Wnt and Notch signalling pathways regulate the formation of sensory hair cells and how modulating their activity induces regenerative potential in the mammalian cochlea.
    No preview · Article · Dec 2015 · International Journal of Developmental Neuroscience
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    • "To investigate whether expression of Jagged1 is critical for renin cell development, we generated mice with conditional deletion of Jagged1 specifically in renin cells. We crossed Jagged1 fl/fl mice (Kiernan et al. 2006) which contain LoxP sites flanking exon 4, the DSL domain of the Jagged1 gene, with EIIa-Cre mice which express cre in the early embryo, resulting in germline deletion of the loxPflanked Jagged1 allele (Jagged1 del/+ ) (Lakso et al. 1996). These mice were then crossed with Jagged1 fl/fl mice and Ren1 d cre/+ mice (Sequeira-Lopez et al. 2004), ultimately generating mice with one deleted Jagged1 allele, one floxed Jagged1 allele, and one copy of Ren1 d cre/+ (Jagged1- del/fl;Ren1d cre/+ ) termed " mutant " animals in this study. "
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    ABSTRACT: The Notch signaling pathway is required to maintain renin expression within juxtaglomerular (JG) cells. However, the specific ligand which activates Notch signaling in renin-expressing cells remains undefined. In this study, we found that among all Notch ligands, Jagged1 is differentially expressed in renin cells with higher expression during neonatal life. We therefore hypothesized that Jagged1 was involved in renin expression and/or vascular integrity. We used a conditional knockout approach to delete Jagged1 in cells of the renin lineage. Deletion of Jagged1 specifically within renin cells did not result in decreased renin production within the kidney. However, animals with conditional deletion of Jagged1 did develop focal kidney fibrosis and elevated blood urea nitrogen. Our data demonstrate that Jagged1-mediated Notch signaling is dispensable in renin cells of the kidney in regard to renin expression. However, deletion of Jagged1 in renin cells descendants affects perivascular-interstitial integrity leading to focal fibrosis and diminished renal function.
    Full-text · Article · Nov 2015
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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.
    Full-text · Article · May 2014 · Development
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