Compartmentalised expression of Delta-like 1 in epithelial somites is required for the formation of intervertebral joints

Ingeborg, Teppner; Sonja, Becker; Angelis, Martin Hrabé de; Gossler, Achim; Beckers, Johannes

doi:10.1186/1471-213x-7-68

Cited by 10 publications

(6 citation statements)

References 68 publications

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“…Dll1 is known to be required for the formation and identity maintenance of the caudal somites [16] and for left-right asymmetry in the embryo [17] . Dll1 expression starts during the mid-streak stage in embryonic mesoderm.…”

Section: Resultsmentioning

confidence: 99%

An ENU-Mutagenesis Screen in the Mouse: Identification of Novel Developmental Gene Functions

et al. 2011

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BackgroundMutagenesis screens in the mouse have been proven useful for the identification of novel gene functions and generation of interesting mutant alleles. Here we describe a phenotype-based screen for recessive mutations affecting embryonic development.Methodology/Principal FindingsMice were mutagenized with N-ethyl-N-nitrosurea (ENU) and following incrossing the offspring, embryos were analyzed at embryonic day 10.5. Mutant phenotypes that arose in our screen include cardiac and nuchal edema, neural tube defects, situs inversus of the heart, posterior truncation and the absence of limbs and lungs. We isolated amongst others novel mutant alleles for Dll1, Ptprb, Plexin-B2, Fgf10, Wnt3a, Ncx1, Scrib(Scrib, Scribbled homolog [Drosophila]) and Sec24b. We found both nonsense alleles leading to severe protein truncations and mutants with single-amino acid substitutions that are informative at a molecular level. Novel findings include an ectopic neural tube in our Dll1 mutant and lung defects in the planar cell polarity mutants for Sec24b and Scrib.Conclusions/SignificanceUsing a forward genetics approach, we have generated a number of novel mutant alleles that are linked to disturbed morphogenesis during development.

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Section: Resultsmentioning

confidence: 99%

An ENU-Mutagenesis Screen in the Mouse: Identification of Novel Developmental Gene Functions

et al. 2011

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“…This finding strongly supports an in vivo inhibitory effect of DLL4 in the PSM, in which Dll4 is ectopically expressed at physiological levels (similar to the endogenous Dll1 levels; Fig 2E ). Skeletal malformations observed in Dll1 Dll4ki/+ mice are distinct from phenotypes observed upon mild overexpression of Dll1 in the paraxial mesoderm that include fused or split vertebral bodies and reduction of costal heads of ribs [ 77 ]. This supports the view that cis -inhibitory DLL4 acts in a dominant-negative manner partially overruling Notch activation by wildtype DLL1 causing axial skeleton defects in Dll1 Dll4ki/+ mice, similar to the effect of a truncated dominant-negative form of DLL1 expressed in the paraxial mesoderm [ 53 ].…”

Section: Discussionmentioning

confidence: 99%

Context-Dependent Functional Divergence of the Notch Ligands DLL1 and DLL4 In Vivo

et al. 2015

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Notch signalling is a fundamental pathway that shapes the developing embryo and sustains adult tissues by direct communication between ligand and receptor molecules on adjacent cells. Among the ligands are two Delta paralogues, DLL1 and DLL4, that are conserved in mammals and share a similar structure and sequence. They activate the Notch receptor partly in overlapping expression domains where they fulfil redundant functions in some processes (e.g. maintenance of the crypt cell progenitor pool). In other processes, however, they appear to act differently (e.g. maintenance of foetal arterial identity) raising the questions of how similar DLL1 and DLL4 really are and which mechanism causes the apparent context-dependent divergence. By analysing mice that conditionally overexpress DLL1 or DLL4 from the same genomic locus (Hprt) and mice that express DLL4 instead of DLL1 from the endogenous Dll1 locus (Dll1Dll4ki), we found functional differences that are tissue-specific: while DLL1 and DLL4 act redundantly during the maintenance of retinal progenitors, their function varies in the presomitic mesoderm (PSM) where somites form in a Notch-dependent process. In the anterior PSM, every cell expresses both Notch receptors and ligands, and DLL1 is the only activator of Notch while DLL4 is not endogenously expressed. Transgenic DLL4 cannot replace DLL1 during somitogenesis and in heterozygous Dll1Dll4ki/+ mice, the Dll1Dll4ki allele causes a dominant segmentation phenotype. Testing several aspects of the complex Notch signalling system in vitro, we found that both ligands have a similar trans-activation potential but that only DLL4 is an efficient cis-inhibitor of Notch signalling, causing a reduced net activation of Notch. These differential cis-inhibitory properties are likely to contribute to the functional divergence of DLL1 and DLL4.

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“…However, the"wavy tail mouse mutant did not develop any of these characteristics, as only the tail was deformed and only during postnatal development. Other mouse models developed defects in the lumbal region or tail already around midgestation, like in the wavy tail mutant these malformation were restricted to the vertebral column but not muscular development (flaky tail (Rothnagel et al, 1994), TgN(Imunsd)379Rpw (Schrick et al, 1995), Sickle tail (Semba et al, 2006), Jun (Behrens et al, 2003), Delta-like I (Teppner et al, 2007), or Tgfbr2 (Baffi et al, 2006)). …”

Section: Discussionmentioning

confidence: 99%

Lasp1 misexpression influences chondrocyte differentiation in the vertebral column

Hermann-Kleiter

Ghaffari-Tabrizi²,

Blumer³

et al. 2009

Int. J. Dev. Biol.

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The mouse mutant wavy tail Tg(Col1a1-lacZ)304ng was created through transgene insertion and exhibits defects of the vertebral column. Homozygous mutant animals have compressed tail vertebrae and wedge-shaped intervertebral discs, resulting in a meandering tail. Delayed closure of lumbar neural arches and lack of processus spinosi have been observed; these defects become most prominent during the transition from cartilage to bone. The spina bifida was resistant to folic acid treatment, while retinoic acid administration caused severe skeletal defects in the mutant, but none in wild type control animals. The transgene integrated at chromosome 11 band D, in an area of high gene density. The insertion site was located between the transcription start sites of the Rpl23 and Lasp1 genes. LASP1 (an actin binding protein involved in cell migration and survival) was found to be produced in resting and hypertrophic chondrocytes in the vertebrae. In mutant vertebrae, temporal and spatial misexpression of Lasp1 was observed, indicating that alterations in Lasp1 transcription are most likely responsible for the observed phenotype. These data reveal a yet unappreciated role of Lasp1 in chondrocyte differentiation during cartilage to bone transition.

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Compartmentalised expression of Delta-like 1 in epithelial somites is required for the formation of intervertebral joints

Cited by 10 publications

References 68 publications

An ENU-Mutagenesis Screen in the Mouse: Identification of Novel Developmental Gene Functions

An ENU-Mutagenesis Screen in the Mouse: Identification of Novel Developmental Gene Functions

Context-Dependent Functional Divergence of the Notch Ligands DLL1 and DLL4 In Vivo

Lasp1 misexpression influences chondrocyte differentiation in the vertebral column

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