1 Division of Mammalian Development, National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK
2 Developmental Biology Unit, The Victor Chang Cardiac Research Institute, 384 Victoria Street, Darlinghurst, NSW 2010, Australia
3 Department of Genetics, Case Western Reserve University, and University Hospitals Cleveland, 10900 Euclid Avenue, Cleveland, OH 44106-4955, USA
*Author for correspondence (e-mail: s.dunwoodie{at}victorchang.unsw.edu.au)
This article is dedicated to Rosa Beddington (March 23, 1956 to May 18, 2001) an extraordinary embryologist and a great friend
Accepted 14 December 2001
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SUMMARY |
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Key words: Notch signalling, Somite, Spondylocostal dysplasia, Pudgy, Dll3, Mouse
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INTRODUCTION |
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The Notch signalling pathway is deployed in three types of processes: lateral inhibition, lineage decisions and boundary formation (Bray, 1998). In vertebrates, somite segmentation relies on boundary formation in rostral presomitic mesoderm, coincident with expression of genes associated with Notch signalling (del Barco Barrantes et al., 1999
). Accordingly, boundary formation with respect to somitogenesis commands considerable interest because, in mouse, core Notch signalling components (Notch1, Dll1, Dll3 and RBPjK) and signalling modifiers [lunatic fringe (Lfng) and presenilin 1] are required for normal somite formation and anterior-posterior somite polarity (Conlon et al., 1995
; Evrard et al., 1998
; Hrabe de Angelis et al., 1997
; Kusumi et al., 1998
; Oka et al., 1995
; Swiatek et al., 1994
; Wong et al., 1997
; Zhang and Gridley, 1998
). In zebrafish, a mutation in deltaD is responsible for the after eight mutant (which makes only the first eight somites), demonstrating that Notch signalling is also required in this species (Holley et al., 2000
).
In presomitic mesoderm, Notch signalling activity is not restricted to boundary formation, but also appears to be required at earlier (albeit interrelated) stages during the development of presomitic mesoderm (Pourquie, 2000). Presomitic mesoderm acquires a prepattern that distinguishes rostral presomitic mesoderm from caudal, and rostrally this culminates in segmentation with anteroposterior polarity being established in a single presomite unit. The periodicity with which this prepattern develops is postulated to require a segmentation clock that oscillates in accordance with the formation of each new somite (Cooke, 1998
; Cooke and Zeeman, 1976
). Genes have been identified in chick (hairy-1), mouse (Lfng, Hes1, Hes7 and Hey2) and in zebrafish (her1, deltaC and deltaD) that produce transcripts that are seen to pass in a caudal to rostral direction (Aulehla and Johnson, 1999
; Forsberg et al., 1998
; Jiang et al., 2000
, Bessho et al., 2001
; Jouve et al., 2000
; Leimeister et al., 2000
; Leimeister et al., 1999
; McGrew et al., 1998
; Palmeirim et al., 1997
). It is likely that Notch signalling is associated with the segmentation clock because these genes are allied with Notch signalling: Fringe in Drosophila acts upstream of the pathway by modifying the response of Notch to ligand binding; deltaC and deltaD are ligands of Notch; and Hairy and Enhancer of Split homologues (chairy-1, Hes1, Hes7 and Hey2) are likely or proven downstream target genes of Notch signalling (Bessho et al., 2001
; de la Pompa et al., 1997
; del Barco Barrantes et al., 1999
; Fleming et al., 1997
; Holley et al., 2000
; Jouve et al., 2000
; Klein and Arias, 1998
; Leimeister et al., 2000
; Leimeister et al., 1999
; Ohtsuka et al., 1999
; Panin et al., 1997
). This oscillatory pattern of gene expression consists of rostral and caudal expression components within the presomitic mesoderm. Characteristically, the rostral domain is condensed and corresponds to a half-somite segment, while the caudal domain is broader and moves rostrally from the caudal presomitic mesoderm. In cases where the core components of Notch signalling have been targeted, null mutant embryos show disrupted oscillatory gene expression within the presomitic mesoderm. The most severe effects are seen in Dll1 and RBPjK mutants, while milder expression perturbations have been reported for Notch1 and the Dll3pu (pudgy) mutant allele (del Barco Barrantes et al., 1999
; Jouve et al., 2000
; Kusumi et al., 1998
; Leimeister et al., 2000
). This suggests that Notch signalling is required to propagate and maintain oscillation of the segmentation clock, probably through a feedback mechanism similar to that identified in Drosophila and nematode (de Celis and Bray, 1997
; Huppert et al., 1997
; Kimble and Simpson, 1997
). However, studies in zebrafish by Jiang and colleagues propose that Notch signalling is not required to establish oscillation within the presomitic mesoderm but rather to keep the oscillations of neighbouring cells synchronised (Jiang et al., 2000
).
To understand how presomitic mesoderm prepatterning and segmentation culminates in somite formation, the role of core components of Notch signalling needs to be examined. In mouse, three Notch ligands are expressed in presomitic mesoderm. While Dll1 and jagged 1 (Jag1) expression is coincident in the posterior half of the forming somite, Dll3 is expressed in the anterior half (del Barco Barrantes et al., 1999; Dunwoodie et al., 1997
; Mitsiadis et al., 1997
; Zhang and Gridley, 1998
), leading to the juxtaposition of Dll1/Jag1 co-expressing cells with Dll3-expressing cells across a forming somite boundary and within a forming somite. Genetic analysis reveals no somitic or vertebral defect in mouse Jag1 null mutants; however, butterfly vertebrae do occur in Alagille Syndrome in which JAG1 is mutated (Krantz et al., 1997
). By contrast, in Dll1 mutants the basic metameric unit within paraxial mesoderm is maintained albeit with a loss of anteroposterior polarity (del Barco Barrantes et al., 1999
; Hrabe de Angelis et al., 1997
; Xue et al., 1999
). In the case of Dll3, pudgy mice have a highly disorganised vertebrocostal skeleton with delayed somite formation (Gruneberg, 1961
; Kusumi et al., 1998
). In humans, spondylocostal dysplasia (SCD) is characterised by similar vertebrocostal defects, and where SCD follows a recessive mode of inheritance, mutations have been reported in the DLL3 gene (Bulman et al., 2000
).
We report the phenotypic analysis of a loss-of-function mutation in mouse Dll3 and demonstrate that this mutation affects the axial skeleton and components of the peripheral nervous system. The skeletal defects are severe and similar to those observed in cases of DLL3-dependent SCD in humans and Dll3/pudgy mice. In addition we show that the two mouse Dll3 mutant alleles, Dll3neo and Dll3pu, are functionally equivalent with respect to the skeletal defects. We use the null Dll3neo allele to show that the skeletal defects originate in aberrant somite formation, which are probably due to an altered segmentation clock in presomitic mesoderm.
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MATERIALS AND METHODS |
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Histology, in situ hybridisation and immunohistochemistry
For histology, embryos were fixed in Bouins fixative, dehydrated, embedded in paraffin wax, sectioned and stained with Hematoxylin-Eosin as described (Kaufman, 1992). Whole-mount RNA in situ hybridisation was performed as described (Harrison et al., 1995
). Probes for the following genes were used: Dll3 (Dunwoodie et al., 1997
), Uncx4.1 (Mansouri et al., 1997
), Cer1 (Biben et al., 1998
), Hes1, Hes5 (Akazawa et al., 1992
; Sasai et al., 1992
), Lfng (Johnston et al., 1997
) and Mesp2 (Saga et al., 1997
). pSPORT1-beta-spectrin2 (6412-8172bp) was linearised with SalI and antisense RNA generated using SP6 RNA polymerase. Skeletal preparations were performed at 14.5 dpc according to Jegalian and De Robertis (Jegalian and De Robertis, 1992
). Whole-mount immunohistochemistry with anti-neurofilament monoclonal antibody 2H3 (Developmental Studies Hybridoma Bank) was performed according to Mark et al. (Mark et al., 1993
).
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RESULTS |
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Defining downstream effectors of Dll3-mediated Notch signalling
As Hes5, Hes1 and Hey1 have been identified as genes responsive to Notch signalling, their expression was examined in Dll3neo/Dll3neo embryos. Hes5 is normally expressed as a band in rostral presomitic mesoderm in the posterior half of the forming somite (de la Pompa et al., 1997; del Barco Barrantes et al., 1999
; Takebayashi et al., 1995
). Analysis of gene expression at 10.5 dpc revealed four distinct patterns of expression in presomitic mesoderm of Dll3/Dll3 and Dll3/Dll3neo embryos. These patterns of expression indicate that Hes5, like closely related Hes1 and Hes7, is dynamically expressed in the presomitic mesoderm (Fig. 7A-D) (Bessho et al., 2001
; Jouve et al., 2000
). By contrast, at 10.5 dpc, Hes5 expression was not detected in presomitic mesoderm in eight out of nine Dll3neo/Dll3neo mutant embryos (Fig. 7E,F). In one embryo, a single faint band was detected in rostral presomitic mesoderm (data not shown). Similarly, at 9.5 dpc, Hes5 expression was not detected in presomitic mesoderm in six out of six Dll3neo/Dll3neo mutant embryos (data not shown). Hes1 is expressed in the caudal half of nascent somites and dynamically in presomitic mesoderm (Jouve et al., 2000
). In the presomitic mesoderm of Dll3/Dll3 and Dll3/Dll3neo embryos, dynamic expression is detected as a broad caudal domain that appears to narrow as it moves rostrally to form a tight band coincident with somite formation (Fig. 7G-I). Rostral expression is evident alone or in combination with this caudal domain of expression, depending upon the stage of the cycle. At 10.5 dpc Dll3/Dll3 embryos exhibited either rostral alone (3/10) or rostral and caudal domains (7/10) of Hes1 expression. Similarly Hes1 expression was detected as a single rostral domain (6/11) or with rostral and caudal domains (5/11) in Dll3/Dll3neo. This pattern of expression was not evident in Dll3neo/Dll3neo mutant embryos because, in ten out of ten, only a single narrow band of Hes1 expression was detected in the rostral presomitic mesoderm (Fig. 7J,K). In addition, no Hes1 expression was detected in the somites where normally it is detected caudally (compare Fig. 7G-I with 7J,K). Hey1 is expressed in the caudal half of the most recently formed somite and in a band in the rostral presomitic mesoderm which narrows as a somite forms (Kokubo et al., 1999
; Leimeister et al., 1999
). Hey1 expression in wild-type (Dll3/Dll3) and heterozygous (Dll3/Dll3neo) embryos reflects this pattern of expression with 10/24 embryos the same as Fig. 7L and 14/24 the same as Fig. 7M. By contrast, in 18 out of 18 Dll3neo/Dll3neo mutant embryos, Hey1 expression appeared static because only a single band of expression was detected in the rostral presomitic mesoderm (Fig. 7N). In addition, expression normally present in the caudal somites was not detectable in most mutants (compare Fig. 7L,M with 7N). In summary, these data demonstrate that Dll3 is required for the normal expression of Hes5, Hes1 and Hey1 in presomitic mesoderm.
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DISCUSSION |
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The developmental origin of skeletal defects associated with SCD lie in the disruption of the segmentation clock within the presomitic mesoderm
Generation of the Dll3neo mutant mouse lines has allowed us to examine the developmental origins of the skeletal defects presented in SCD. The core SCD phenotype is characterised by multiple hemi-vertebrae with rib fusions and deletions. The developmental origins of this phenotype reside in aberrant somite formation a defect that appears grounded in the loss of the oscillatory mechanism that drives the regular periodicity with which somites are formed. The molecular analysis of Dll3neo/Dll3neo embryos identifies genes associated with Notch signalling, whose normal expression in the presomitic mesoderm is dependent upon Dll3 function. These include Lfng, Hes5, Hes1 and Hey1, and therefore these are candidate genes responsible for cases of SCD that show no link to DLL3/19q13.
Are Dll1 and Dll3 distinct ligands of Notch in paraxial mesoderm?
Both Dll1 and Dll3 are required for normal somite formation and correct specification of anteroposterior polarity within the presomitic mesoderm (Gruneberg, 1961; Hrabe de Angelis et al., 1997
; Kusumi et al., 1998
) (Figs 5, 6). As Dll1 and Dll3 are both ligands of Notch, what evidence is there that they are distinct ligands that elicit different downstream responses? This study shows that markers of anterior (Cer1) and posterior (Uncx4.1) somite identity are expressed at normal levels in the absence of Dll3, but that the periodic expression of Uncx4.1 and Cer1, which is characteristic of anteroposterior polarity, is lost (Fig. 6 and summarised in Fig. 9). By contrast, anteroposterior identity is lost in Dll1 mutants, as Uncx4.1 is not detected, while Cer1 (and EphA4 another marker of anterior) are severely downregulated (del Barco Barrantes et al., 1999
) (Fig. 9). In addition, we present evidence to suggest that Dll1 and Dll3 elicit distinct responses from genes associated with Notch signalling. For example, a loss-of-function mutation in Dll1 results in severely downregulated (and largely undetected) expression of Lfng, Hes5, Hes1, Hey1, Mesp1 and Mesp2 in presomitic mesoderm (del Barco Barrantes et al., 1999
; Jouve et al., 2000
; Kokubo et al., 1999
) (Fig. 9). By contrast, with the exception of Hes5, the expression of each of these genes is readily detected in presomitic mesoderm of Dll3 null mutants (Figs 5-7, 9; Mesp1 was not examined). That Dll1 and Dll3 may be distinct is further supported by the fact that Dll3 is a highly divergent Delta homologue (Dunwoodie et al., 1997
) and has only 18% identity to the Notch binding DSL of Dll1, compared with the 51% identity between Dll4 and Dll1. It is, however, possible that when Dll1 and Dll3 mutants are compared that some of the observed differences in gene expression do not indicate discrete functions for these ligands but rather reflect the possibility that Dll1 and Dll3 perform the same function and affect the expression of specific genes to different extents. As Dll1 and Dll3 are differentially expressed in presumptive and nascent somites, this issue could best be addressed by placing the Dll1 cDNA under the regulatory control of Dll3 or vice versa using a cDNA knock-in approach.
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A comparison of Dll3 and deltaD mutants
The mutant phenotype of Dll3 resembles that of deltaD (after eight) in zebrafish at a number of levels. First, in both mutants somite formation occurs in the first instance with what appears to be the correct periodicity. This is followed by delayed somite formation in Dll3 mutants, and lack of somite formation in deltaD mutants. However, even though metamerism was apparent in Dll3 mutants, borders between somites were not evident and condensation of paraxial mesoderm into somites was reduced compared with wild type (Fig. 5). That somitogenesis is not completely normal is supported by the fact that the vertebra caudal to and including cervical 1 (which is comprised of the anterior part of the fifth formed somite) was not properly formed. Second, marker gene expression indicates that paraxial mesoderm in Dll3 and deltaD mutants has both anterior (Dll3 Cer1 and Mesp2; deltaD mesp-a, EphA4, fgf8 and deltaD) and posterior (Dll3 Uncx4.1 and Cited1; deltaD ephrin-B2 and MyoD) character (Fig. 6, data not shown) (Durbin et al., 2000). Third, although paraxial mesoderm has anterior and posterior identity in both mutants, like cells are not grouped and spaced periodically (Fig. 6) (Durbin et al., 2000
). Finally, both mutants show disrupted expression of genes expressed in a cyclical manner in the presomitic mesoderm. In Dll3 mutants, Lfng, Hes1 and Hes5 expression is disrupted, while in deltaD, her1 expression is disrupted. As mutant expression of Lfng, Hes1 and her1 consists of what appears to be a static band in the rostral presomitic mesoderm in the absence of caudal expression, there is potentially a common mechanism that is responsible for the oscillatory gene expression in presomitic mesoderm (Fig. 7) (Holley et al., 2000
).
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ACKNOWLEDGMENTS |
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