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

Abstract

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.

Defects in sensory organ morphogenesis and generation of cochlear hair cells in Gata3-deficient mouse embryos

“…Jag1 is expressed from early on in the prosensory and later in the distinct sensory epithelia and mutations in Jag1 have resulted in missing or reduced cristae as well as in severely reduced utricular macula but in a mildly affected saccular macula (Kiernan et al, 2001(Kiernan et al, , 2006. In addition, the crista morphology was often abnormal with the non-sensory cruciate eminence missing (Kiernan et al, 2001;2006) as in Gata3À/À ears (Fig.…”

Strategies to regenerate hair cells: Identification of progenitors and critical genes

“…In addition, the expression of Jagged1 becomes visible soon after this, before cell differentiation, suggesting an additional role of the Notch pathway at early stages of inner ear development. Indeed, in the inner ear of conditional knock-out mice, where Jag1 loxp/loxp mice were crossed with Foxg1-cre mice, Sox2 and p27 Kip1 , two early markers of the future organ of Corti, were shown to be down-regulated and a complete loss of outer HCs was observed (Brooker et al, 2006;Kiernan et al, 2006). Jagged1 is also initially expressed in the prosensory region of the cochlea and becomes down-regulated in the nascent organ of Corti by E14.5 when the cells exit the cell cycle and differentiate (Kiernan et al, 2006).…”

Somatostatin Receptor Types 1 and 2 in the Developing Mammalian Cochlea

“…In turn, the appearance of each organ has been identified by the observation of specific gene expression in sensory regions before histological differentiation. The Notch signaling pathway has multiple roles during inner ear development [3,4]. Notch signaling activates the transcription of Hes5, a homologue of Drosophila hairy and enhancer of split proteins, which encodes a basic helix-loop-helix transcriptional repressor.…”