TY - JOUR

T1 - Divergence of zebrafish and mouse lymphatic cell fate specification pathways

AU - van Impel, Andreas

AU - Zhao, Zhonghua

AU - Hermkens, Dorien M A

AU - Roukens, M Guy

AU - Fischer, Johanna C

AU - Peterson-Maduro, Josi

AU - Duckers, Henricus

AU - Ober, Elke

AU - Ingham, Philip W

AU - Schulte-Merker, Stefan

PY - 2014/3

Y1 - 2014/3

N2 - 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.

AB - 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.

KW - Animals

KW - Animals, Genetically Modified

KW - COUP Transcription Factor II

KW - Cell Differentiation

KW - Cell Lineage

KW - Endothelial Cells

KW - Gene Expression Regulation, Developmental

KW - Homeodomain Proteins

KW - Lymphangiogenesis

KW - Lymphatic Vessels

KW - Mice

KW - Mice, Knockout

KW - Mutation

KW - SOXF Transcription Factors

KW - Species Specificity

KW - Tumor Suppressor Proteins

KW - Zebrafish

KW - Zebrafish Proteins

U2 - 10.1242/dev.105031

DO - 10.1242/dev.105031

M3 - Journal article

C2 - 24523456

VL - 141

SP - 1228

EP - 1238

JO - Development

JF - Development

SN - 0950-1991

IS - 6

ER -