Divergence of zebrafish and mouse lymphatic cell fate specification pathways

van Impel, A., Zhao, Z., Hermkens, D.M., Roukens, M.G., Fischer, J.C., Peterson-Maduro, J., Duckers, H., Ober, E.A., Ingham, P.W., and Schulte-Merker, S.
Development (Cambridge, England)   141(6): 1228-1238 (Journal)
Registered Authors
Fischer, Johanna, Ingham, Philip, Ober, Elke, Peterson-Maduroe, Josi, Schulte-Merker, Stefan, van Impel, Andreas, Zhao, Zhonghua
Coup-TFII, Lymphangiogenesis, Nr2f2, Prox1, Sox18
MeSH Terms
  • Animals
  • Animals, Genetically Modified
  • COUP Transcription Factor II/deficiency
  • COUP Transcription Factor II/genetics
  • COUP Transcription Factor II/metabolism
  • Cell Differentiation
  • Cell Lineage
  • Endothelial Cells/cytology
  • Endothelial Cells/metabolism
  • Gene Expression Regulation, Developmental
  • Homeodomain Proteins/genetics
  • Homeodomain Proteins/physiology*
  • Lymphangiogenesis/genetics
  • Lymphangiogenesis/physiology*
  • Lymphatic Vessels/cytology
  • Lymphatic Vessels/metabolism
  • Mice
  • Mice, Knockout
  • Mutation
  • SOXF Transcription Factors/deficiency
  • SOXF Transcription Factors/genetics
  • SOXF Transcription Factors/metabolism
  • Species Specificity
  • Tumor Suppressor Proteins/deficiency
  • Tumor Suppressor Proteins/genetics
  • Tumor Suppressor Proteins/physiology*
  • Zebrafish/genetics
  • Zebrafish/growth & development*
  • Zebrafish/physiology
  • Zebrafish Proteins/deficiency
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
  • Zebrafish Proteins/physiology*
24523456 Full text @ Development

In mammals, the homeodomain transcription factor Prox1 acts as the central regulator of lymphatic cell fate. Its restricted expression in a subset of cardinal vein cells leads to a switch towards lymphatic specification and hence represents a prerequisite for the initiation of lymphangiogenesis. Murine Prox1-null embryos lack lymphatic structures, and sustained expression of Prox1 is indispensable for the maintenance of lymphatic cell fate even at adult stages, highlighting the unique importance of this gene for the lymphatic lineage. Whether this pre-eminent role of Prox1 within the lymphatic vasculature is conserved in other vertebrate classes has remained unresolved, mainly owing to the lack of availability of loss-of-function mutants. Here, we re-examine the role of Prox1a in zebrafish lymphangiogenesis. First, using a transgenic reporter line, we show that prox1a is initially expressed in different endothelial compartments, becoming restricted to lymphatic endothelial cells only at later stages. Second, using targeted mutagenesis, we show that Prox1a is dispensable for lymphatic specification and subsequent lymphangiogenesis in zebrafish. In line with this result, we found that the functionally related transcription factors Coup-TFII and Sox18 are also dispensable for lymphangiogenesis. Together, these findings suggest that lymphatic commitment in zebrafish and mice is controlled in fundamentally different ways.

Genes / Markers
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Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes