Human Molecular Genetics, 2001, Vol. 10, No. 5 507-512
© 2001 Oxford University Press
The mouse slalom mutant demonstrates a role for Jagged1 in neuroepithelial patterning in the organ of Corti
1MRC Mammalian Genetics Unit and Mouse Genome Centre, Harwell, Oxon OX11 ORD, UK, 2MRC Institute of Hearing Research, Nottingham NG7 2RD, UK, 3Department of Biotechnology and Genetics and 4Department of Neuroscience, SmithKline Beecham Pharmaceuticals, Essex CM19 5AW, UK
Received 7 November 2000; Revised and Accepted 12 January 2001.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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The Notch signalling pathway has recently been implicated in the development and patterning of the sensory epithelium in the cochlea, the organ of Corti. As part of an ongoing large-scale mutagenesis programme to identify new deaf or vestibular mouse mutants, we have identified a novel mouse mutant, slalom, which shows abnormalities in the patterning of hair cells in the organ of Corti and missing ampullae, structures that house the sensory epithelia of the semicircular canals. We show that the slalom mutant carries a mutation in the Jagged1 gene, implicating a new ligand in the signalling processes that pattern the inner ear neuro-epithelium.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Lateral inhibition has been implicated as the proposed mechanism by which decisions are made regarding sensory hair cell versus supporting cell in the sensory patches of the developing inner ear (1,2). Mouse mutations have enabled the roles of the various players in this pathway to be determined. Mice homozygous for a targeted null mutation of Jagged2 (Jag2) develop supernumerary hair cells (3), whereas a mutation in lunatic fringe (Lfng) partially suppresses the effects of the Jag2 mutation (4). Moreover, the expression patterns of Notch1 and ligands, Jag2 and Delta1 (Dll1), are consistent with them playing a role in lateral inhibition that may determine the ordered array of sensory hair cells and supporting cells that is the organ of Corti responsible for auditory transduction (1,3,5). In addition, Delta–Notch signalling has been implicated in lateral inhibition in sensory cell differentiation from studies in zebrafish (6). Misregulation of delta genes and a Serrate homologue have been observed in the zebrafish mind bomb mutant where the ear sensory patches consist solely of hair cells. There is also a deltaA zebrafish mutant which has increased numbers of hair cells (7). Whereas the downstream pathways of Notch signalling within the sensory epithelium in the cochlea are less well characterized, they may include proneural genes, such as Math1, and the HES family of bHLH proteins (8). Mouse mutants carrying a deletion of Math1 fail to develop hair cells (9).
Two large-scale ENU mouse mutagenesis programmes have recently been described whose purpose has been to undertake a systematic and genome-wide effort to recover a large number of novel mutations affecting a diverse array of phenotypic areas involved with genetic disease (10,11). One feature of these programmes has been the recovery of a large number of dominant phenotypes showing deafness and/or vestibular dysfunction as models of human genetic deafness. We have characterized from this screen a new dominant phenotype, slalom, and identified the underlying gene. slalom is encoded by the Jag1 gene implicating a new signalling molecule in the pathways that determine the patterning of the neuro-epithelium in the inner ear.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Identification and characterization of the slalom mutation
The ENU mutagenesis programme carried out within the UK incorporated a comprehensive phenotype assessment tool, SHIRPA, involving a battery of up to 40 simple tests, used to detect novel phenotypes in the areas of lower motoneuron/muscle function, spinocerebellar function, sensory function, neuropsychiatric function and autonomic function (12,13). As part of the panel of tests to determine sensory function we included a click-box test to assess deafness along with a number of tests to investigate vestibular function (see http://www.mgu.har.mrc.ac.uk/mutabase/). Over 60 dominant phenotypes showing deafness and/or vestibular dysfunction have been identified to date and many inheritance tested, including the mutant slalom.
The slalom mutant showed a positive Preyer response to the click-box test, indicating that it was not deaf. However, slalom did show subtle headweaving/shaking and poor negative geotaxis indicative of a vestibular defect. Detailed structural and ultrastructural studies (Fig. 1) demonstrated a variety of inner ear anomalies in both the vestibular system and the organ of Corti. Firstly, slalom shows truncation of either the posterior or anterior semi-circular canals (Fig. 1F). Occasionally, truncation of both canals is also observed (Fig. 1E). When either or both canals are truncated, the corresponding posterior and/or anterior ampullae are absent. These vestibular defects presumably contribute to the headweaving/shaking behaviour of the slalom mutant. We also used scanning electron microscopy (SEM) to examine the organ of Corti of slalom mutants. slalom shows reduced numbers of outer hair cells. In some areas, the organ of Corti completely lacks one row of outer hair cells (Fig. 1B); in other regions, isolated outer hair cells are missing from one of the three rows, row 3 (Fig. 1C). In addition, occasional supernumary and atypical hair cells with outer hair cell morphology are seen within the inner hair cell row (Fig. 1B). Outer hair cell counts (Fig. 1G) reveal a significant decrease (15%) in the basal turns and 17% decrease in the apical turns of slalom mice. Inner hair cell counts reveal a significant increase in the number of inner hair cells in the base of the slalom cochlea, largely due to additional inner hair cells which appear to form a second row, although this increase was not observed in the apical regions of the cochlea (Fig. 1G). Moreover, the atypical hair cells within the inner hair cell row of both the base and apex of slalom cochlea are not seen in the controls.
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Genetic mapping and positional candidate cloning of slalom
We undertook the genetic mapping of the slalom mutant using a speed backcross approach (10) which takes advantage of the fact that founder mice from the mutagenesis programme are BALB/c/C3H hybrids. Backcross progeny are generated using sperm from the founder or their male progeny (if the founder is not male) to fertilize C3H eggs. We employed a rapid genotyping approach involving pooling of affected backcross progeny DNAs and fluorescent genotyping using a panel of 100 microsatellite markers (14). Initial linkage to chromosome 2 was confirmed by genotyping of individual DNAs and the slalom mutation was shown to lie between D2Mit272 and a cluster of markers—D2Mit106/D2Mit34/D2Mit133—in the region of the Jagged1 (Jag1) gene (data not shown). Given this map location, there were several reasons to consider Jag1 a strong positional candidate for slalom. Firstly, Alagille’s syndrome patients are heterozygous for mutations in the JAG1 gene and, amongst a variety of clinical features, they demonstrate partial or missing posterior canals (15,16). Occasionally, the anterior canal is also affected. Secondly, the coloboma mouse mutation is caused by a deletion on mouse chromosome 2 which encompasses Jag1 (17). coloboma shows head-shaking behaviour. Finally, Jag1 is known to be expressed during early development of the organ of Corti throughout the developing sensory patch, later localizing to the supporting cells (3). Although, a Jag1 knock-out has been constructed (Jag1dDSL) neither behavioural anomalies indicative of vestibular dysfunction nor detailed ultrastructural analyses of the inner ear were reported (17). However, examination of homozygous embryos (Jag1dDSL/Jag1dDSL) indicated defects in embryonic and yolk-sac vasculature (see below).
We carried out mutation analysis of the Jag1 gene by RT–PCR of kidney RNA from both wild-type (BALB/c and BALB/c/C3H genomes) and slalom mutants (Fig. 2). RT–PCR products covering the entire coding sequence were cloned and sequenced. A C
T missense mutation was identified that causes a proline to serine change at codon 269 in the second epidermal growth factor (EGF)-like repeat. This change was not identified in the parental genomes. This proline residue is conserved in all Jagged/Serrate homologues characterized to date across a wide variety of species (Fig. 3D). Both the first and second EGF-like repeats appear to play a role in modulating the affinity of interaction between Jagged1 and Notch receptors (18).
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Vascular defects and neural tube anomalies in slalom homozygotes
Identification of the slalom mutation allowed us to unambiguously type embryonic homozygotes and to compare their phenotype with Jag1dDSL/Jag1dDSL embryos and with wild-type (Fig. 3). Whereas Jag1dDSL/Jag1dDSL embryos die at E11.5 (17), slalom homozygotes survive to E12.5. slalom homozygote embryos did not demonstrate the craniofacial haemorrhaging observed in Jag1dDSL/Jag1dDSL embryos (17), but there appeared to be reduced large vasculature in the yolk-sac similar to the Jag1dDSL/Jag1dDSL phenotype in all 11 homozygotes identified (Fig. 3B and D). In addition, some slalom E12.5 homozygotes (3/11 from a total of 39 embryos dissected at E11.5 and E12.5), appear to show neural tube defects, similar to Notch1 mutant homozygotes (19) (Fig. 3E). Also two homozygote embryos were found that were retarded in development, lagging at least two days behind their siblings.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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We have demonstrated that a mutation in the Jag1 gene leads to disturbances of the patterning of the organ of Corti in the inner ear, characterized by reduced numbers of outer hair cells, particularly in the third row, and loss of sensory structures in the vestibular system. A similar phenotype has also been seen in the Headturner mutant, isolated in the German mutagenesis screen, which also carries a mutation in Jag1 (11; A.E. Kiernan et al., submitted). This reduction in the numbers of outer hair cells we see in slalom is in contrast to the increase to four rows observed in the Jag2 mutant (3). In the slalom mutant we see a significant increase of inner hair cells in the base (
15%), but not as many as in the Jag2 mutant, where there is an increase of 50% of the inner hair cell number (3). For outer hair cells, it would appear that Jag1 and Jag2 may play reciprocal roles in signalling from the supporting and hair cells, respectively. Both Notch1 and Jag1 are expressed primarily in the supporting cells of the developing organ of Corti at E18 (4,20). At the same time, Jag2 expression is detectable in both developing inner and outer hair cells. A model of lateral inhibition mediated by Notch signalling has been proposed based on the pattern of cell types in the epithelium, in which every hair cell is surrounded by supporting cells (1–3,21). The model assumes that the hair cell phenotype is the default fate in the developing cells in the organ of Corti. Jag2 is expressed in a subset of cells activating Notch in neighbouring cells and preventing their development as hair cells. Inactivation of Jag2 leads to the development of additional hair cells, as the lateral inhibition model would predict. Equally, mice heterozygous for a Notch mutation also show an increase in hair cells consistent with Jag2 signalling playing a role in maintaining supporting cell fate (4). It is now clear from the analysis of the slalom mutant that we need to consider the role of Jag1 in the signalling pathways in the developing organ of Corti.
On the basis of the phenotypic effects of mutations in the Jag1 and Jag2 genes and taking into account their expression patterns, we have developed one possible model for Jag1 and Jag2 signalling in the patterning of the organ of Corti (Fig. 4). We propose that Jag1 may play a role in determining supporting cell fate, but also may signal (via an unknown receptor) to adjacent developing sensory cells to inhibit Jag1 expression in these cells. Signalling of Jag2 from developing sensory cells via Notch may reinforce expression of Jag1 in supporting cells, while down-regulating Jag2, thus providing both a positive and negative feedback loop to establish the differentiation of supporting and sensory cells. In Jag2 mutants, Jag2 signalling to adjacent cells is lost and as a consequence Jag1 expression in supporting cells may not be maintained and hair cells develop. We hypothesize that slalom is a hypomorphic mutant leading to reduced Jag1 levels in supporting cells. Indeed, the proline to serine change observed in the slalom mutant seems likely to cause loss of function by affecting the role of the second EGF repeat in binding to Notch receptors. Under our proposed model, a reduction in Jag1 signalling from supporting cells would lead to raised levels of expression of Jag1 in developing hair cells and as a consequence, some may fail to differentiate properly as observed in the slalom mutant.
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It has been reported recently that down-regulation of Jag1 in antisense experiments, with cultures of the developing neuro-epithelium, leads to an increase in numbers of both inner and outer hair cells (20), and in contrast leads to the reduction in outer hair cells observed in the slalom mutant. However, these differences would be explicable if slalom is, as we suggest, a loss of function, semi-dominant mutation. The slalom hair cell phenotype is observed in heterozygotes, presumably with levels of Jag1 activity
50% of wild-type. If Jag1 is indeed important for determining the fate of the supporting cells, as well as signalling to neighbouring sensory cells, a reduction in the level of Jag1 could reduce the number of cells developing into hair cells, whereas the complete loss of Jag1 could lead to an increase in hair cell number (Fig. 4). Our proposed model assumes that neither Jag1 nor Jag2 are completely responsible for determining cell fate in the developing organ of Corti (if they were, there would be either no hair cells or no supporting cells in Jag1 and Jag2 mutants, respectively), but instead act in a combinatorial manner along with other signalling molecules to tilt the balance towards a hair cell or supporting cell fate. Furthermore, counting supporting cells is difficult, so we have no clear evidence whether there are additional supporting cells in the Jag1 mutants or reduced numbers of supporting cells in Jag2 mutants. Scanning electron microscopy of the slalom mutant does not reveal any disturbances in the relationship between the outer hair cells and the supporting cells around them. It is clear that further studies are needed to determine why the extra inner hair cells are present, as our proposed model does not fully explain all of these observations. In conclusion, the identification of the slalom mutant demonstrates that Jag1 signalling has a pivotal role in the normal development of the organ of Corti and specification of some of the vestibular sensory epithelia. It will now be important to investigate further its relationship to other members of the Notch signalling pathway in the inner ear and their roles in the development of both the auditory and balance system of mammals.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Mapping and mutation screening
We generated backcross progeny for mapping by mating the founder F1 Slalom mutant to C3H, this cross also serving as an inheritance test. We phenotyped all progeny for headweaving behaviour. Thirty DNAs were pooled from affected individuals and then genome scanned as described (10,14). Once a region of linkage was identified, we confirmed the map position by genotyping and haplotype analysis of individual affected backcross progeny. We carried out mutation analysis of the Jag1 gene by RT–PCR of kidney RNA, followed by cloning of RT–PCR products and sequencing. Results were confirmed by direct sequencing of PCR products.
Genotyping of embryos
Embryos were aged based on the day of the vaginal plug being E0.5. We genotyped embryos using the DdeI restriction site introduced by the mutation (Fig. 3B). Embryo DNA was amplified using the primers: 5'-CTGTACTGCGACAAGTGCATC-3' and 5'-TTGTCACAGAGCTGTCCACC-3' and PCR products digested with DdeI prior to gel electrophoresis.
Paintfilling
We carried out paintfills essentially as described (22). We decapitated both wild-type and +/Slm mice and then fixed the heads in Bodians fixative (75% ethanol, 5% formalin, 5% glacial acetic acid) overnight followed by washing (minimum 2 h for each wash) twice in each of the following solutions: 75, 95 and 100% ethanol. We then bisected heads and cleared them overnight in methyl salicylate. We injected the endolymphatic compartment of the inner ears via either the common crus or cochlea employing a pulled glass capillary pipette (20–40 µm diameter) filled with 1% gloss paint in methyl salicylate. Finally, we dissected the ears free of the skull and photographed them in methyl salicylate using an Olympus DP10 digital camera.
SEM
We prepared samples for SEM using the osmium tetroxide-thiocarbohydrazide (OTOTO) method as described previously (23,24). Briefly, we dissected inner ears in fixative (2.5% glutaraldehyde in 0.1M phosphate buffer pH 7.2), piercing the windows and apex of the cochlea and samples were allowed to fix for 4 to 5 h rotating at 4°C. We then washed ears overnight in 0.1 M phosphate buffer. For preparation of the organ of Corti, we removed the outer bony shell and stria vascularis. After OTOTO, we dried specimens at critical point, sputter coated and then examined them under a Phillips XL30 scanning electron microscope.
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ACKNOWLEDGEMENTS |
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We thank Karen Avraham for Jag1 primers. This work was supported by the Medical Research Council, SmithKline Beecham and the EC (contract BMH4-CT97-2715).
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FOOTNOTES |
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+ These authors contributed equally to this work
§ To whom correspondence should be addressed. Tel: +44 1235 824541; Fax: +44 1235 824542; Email: s.brown@har.mrc.ac.uk
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