Cyclical expression of the Notch/Wnt regulator Nrarp requires modulation by Dll3 in somitogenesis

William Sewell, Duncan B. Sparrow, Allanceson J. Smith, Dorian M. Gonzalez, Eric F. Rappaport, Sally L. Dunwoodie, Kenro Kusumi

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Delta-like 3 (Dll3) is a divergent ligand and modulator of the Notch signaling pathway only identified so far in mammals. Null mutations of Dll3 disrupt cycling expression of Notch targets Hes1, Hes5, and Lfng, but not of Hes7. Compared with Dll1 or Notch1, the effects of Dll3 mutations are less severe for gene expression in the presomitic mesoderm, yet severe segmentation phenotypes and vertebral defects result in both human and mouse. Reasoning that Dll3 specifically disrupts key regulators of somite cycling, we carried out functional analysis to identify targets accounting for the segmental phenotype. Using microdissected embryonic tissue from somitic and presomitic mesodermal tissue, we identified new genes enriched in these tissues, including Limch1, Rhpn2, and A130022J15Rik. Surprisingly, we only identified a small number of genes disrupted by the Dll3 mutation. These include Uncx, a somite gene required for rib and vertebral patterning, and Nrarp, a regulator of Notch/Wnt signaling in zebrafish and a cycling gene in mouse. To determine the effects of Dll3 mutation on Nrarp, we characterized the cycling expression of this gene from early (8.5 dpc) to late (10.5 dpc) somitogenesis. Nrarp displays a distinct pattern of cycling phases when compared to Lfng and Axin2 (a Wnt pathway gene) at 9.5 dpc but appears to be in phase with Lfng by 10.5 dpc. Nrarp cycling appears to require Dll3 but not Lfng modulation. In Dll3 null embryos, Nrarp displayed static patterns. However, in Lfng null embryos, Nrarp appeared static at 8.5 dpc but resumed cycling expression by 9.5 and dynamic expression at 10.5 dpc stages. By contrast, in Wnt3a null embryos, Nrarp expression was completely absent in the presomitic mesoderm. Towards identifying the role of Dll3 in regulating somitogenesis, Nrarp emerges as a potentially important regulator that requires Dll3 but not Lfng for normal function.

Original languageEnglish (US)
Pages (from-to)400-409
Number of pages10
JournalDevelopmental Biology
Volume329
Issue number2
DOIs
StatePublished - May 15 2009

Fingerprint

Somites
Mutation
Embryonic Structures
Genes
Mesoderm
Phenotype
Gene Expression
Wnt Signaling Pathway
Ribs
Zebrafish
Mammals
Ligands

Keywords

  • Axin2
  • Delta-like 3
  • Dll3
  • Hnrnpl
  • Lfng
  • Limch1
  • Notch
  • Nrarp
  • Oscillatory
  • Presomitic mesoderm
  • Rhpn2
  • Segmentation
  • Somitogenesis
  • Uncx
  • Wnt

ASJC Scopus subject areas

  • Developmental Biology
  • Cell Biology
  • Molecular Biology

Cite this

Sewell, W., Sparrow, D. B., Smith, A. J., Gonzalez, D. M., Rappaport, E. F., Dunwoodie, S. L., & Kusumi, K. (2009). Cyclical expression of the Notch/Wnt regulator Nrarp requires modulation by Dll3 in somitogenesis. Developmental Biology, 329(2), 400-409. https://doi.org/10.1016/j.ydbio.2009.02.023

Cyclical expression of the Notch/Wnt regulator Nrarp requires modulation by Dll3 in somitogenesis. / Sewell, William; Sparrow, Duncan B.; Smith, Allanceson J.; Gonzalez, Dorian M.; Rappaport, Eric F.; Dunwoodie, Sally L.; Kusumi, Kenro.

In: Developmental Biology, Vol. 329, No. 2, 15.05.2009, p. 400-409.

Research output: Contribution to journalArticle

Sewell, W, Sparrow, DB, Smith, AJ, Gonzalez, DM, Rappaport, EF, Dunwoodie, SL & Kusumi, K 2009, 'Cyclical expression of the Notch/Wnt regulator Nrarp requires modulation by Dll3 in somitogenesis', Developmental Biology, vol. 329, no. 2, pp. 400-409. https://doi.org/10.1016/j.ydbio.2009.02.023
Sewell W, Sparrow DB, Smith AJ, Gonzalez DM, Rappaport EF, Dunwoodie SL et al. Cyclical expression of the Notch/Wnt regulator Nrarp requires modulation by Dll3 in somitogenesis. Developmental Biology. 2009 May 15;329(2):400-409. https://doi.org/10.1016/j.ydbio.2009.02.023
Sewell, William ; Sparrow, Duncan B. ; Smith, Allanceson J. ; Gonzalez, Dorian M. ; Rappaport, Eric F. ; Dunwoodie, Sally L. ; Kusumi, Kenro. / Cyclical expression of the Notch/Wnt regulator Nrarp requires modulation by Dll3 in somitogenesis. In: Developmental Biology. 2009 ; Vol. 329, No. 2. pp. 400-409.
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