Polydom Is an Extracellular Matrix Protein Involved in Lymphatic Vessel Remodeling

Abstract

Polydom affects remodeling of lymphatic vessels in both mouse and zebrafish. Polydom deposited around lymphatic vessels seems to ensure Foxc2 upregulation in lymphatic endothelial cells, possibly via the Ang-2 and Tie1/Tie2 receptor system.

Lymphatic Vessel Network Structure and Physiology

“…Foxc2 expression was decreased in the polydom -/- mice. Those animals lacked maturation of collecting lymphatic vessels and lymphatic valves (522, 727). It was mentioned previously that Notch1 negatively regulates Prox1 expression during LEC specification.…”

A New Conserved Player in Lymphatic Morphogenesis

“…Rescue experiments with bacterial artificial chromosome (BAC) transgenes, as well as mRNA, confirmed that lymphatic defects were due to loss of svep1 function. In parallel, Morooka et al applied genome editing to generate a targeted deletion in zebrafish svep1 , which led to the same defects in thoracic duct formation 10 , further confirming the requirement for this gene in lymphatic development. More careful assessment of the mutant phenotype in zebrafish revealed that early lymphatic specification was unaffected, with Prox1 expression apparent in progenitors in the cardinal vein, although sprouting of these lymphatic progenitors was deficient.…”

“…As noted above, Morooka et al initially identified Svep1 as a binding partner for integrin α9β1, which itself is required for lymphatic valve morphogenesis 9 . However, svep1 mutant mice show much broader defects in the lymphatic system that those associated with integrin α9 -deficiency 10 , while integrin α9 mutant zebrafish do not recapitulate the svep1 mutant phenotype 11 . These results suggest that Svep1 acts independently of integrin α9 during lymphatic maturation, although a functional interaction during valve formation cannot be ruled out.…”

“…In this issue of Circulation Research, two groups have taken advantage of both zebrafish and mouse models to identify a new molecule that is essential for proper formation of the lymphatic system 10, 11 . In the course of a forward genetic screen, Karpanen et al identified a zebrafish mutant that failed to form a thoracic duct, an early lymphatic vessel formed during development in this model 11 .…”

Genome Sequencing Unveils a New Regulatory Landscape of Platelet Reactivity

“…Collectively, these results suggest that SVEP1 may have previously unappreciated and multifactorial roles in contributing to CVD. Homozygous Svep1 -/mice die from edema, and heterozygous mice, as well as zebrafish, experience arterial and lymphatic vessel malformations [28][29][30] . Consistent with previous investigations 31 , RNAseq data in a subset of GeneSTAR participants do not indicate expression of SVEP1 in platelets.…”