Fetal nuchal edema and developmental anomalies caused by gene mutations in mice

Abstract

Fetal nuchal edema, a subcutaneous accumulation of extracellular fluid in the fetal neck, is detected as increased nuchal translucency (NT) by ultrasonography in the first trimester of pregnancy. It has been demonstrated that increased NT is associated with chromosomal anomalies and genetic syndromes accompanied with fetal malformations such as defective lymphatic vascular development, cardiac anomalies, anemia, and a wide range of other fetal anomalies. However, in many clinical cases of increased NT, causative genes, pathogenesis and prognosis have not been elucidated in humans. On the other hand, a large number of gene mutations have been reported to induce fetal nuchal edema in mouse models. Here, we review the relationship between the gene mutants causing fetal nuchal edema with defective lymphatic vascular development, cardiac anomalies, anemia and blood vascular endothelial barrier anomalies in mice. Moreover, we discuss how studies using gene mutant mouse models will be useful in developing diagnostic method and predicting prognosis.

Keywords: cardiac anomaly; fetal nuchal edema; gene mutations; lymphatic vascular development; mouse embryos.

FIGURE 1

Developmental anomalies causing fetal nuchal edema in mice. BV, blood vessel; H, heart; JLS, jugular lymph sac; JV, jugular vein; L, liver; LVN, lymphatic vascular network; NT, nuchal translucency.

FIGURE 2

Transcriptional networks in specification of LEC progenitors. Prox1 is a master transcriptional regulator gene of LEC specification. Several transcription factors (Sox18, Coup-TFII, Hhex) and Cpt1a-modulated histone acetylation regulate Prox1 expression. Causative genes for fetal nuchal edema in mice are surrounded by square.

FIGURE 3

VEGFR3 signaling in migration and proliferation of LEC progenitors. VEGFR3 functions as a main signaling receptor for migration and proliferation of LEC progenitors. Ccbe1 and Adamts3 cleave pro-VEGF-C and produce active form that allows binding to VEGFR3. Binding of VEGF-C to VEGFR3 results in tyrosine phosphorylation, which in turn activates Ras/Raf signaling. Raf activity is negatively regulated by Spred1 and Spred2. VEGFR3 signaling is also regulated by β1 integrin in a VEGF-C independent manner. β1 integrin interaction to VEGFR3 is inhibited by Ilk, but upon mechanical stretch, the complex of β1 integrin and Ilk is transiently disrupted, which in turn promotes VEGFR3 phosphorylation. Causative genes for fetal nuchal edema in mice are surrounded by square.