Biology subjects

Martucciello, S.

Publications and source records attributed to Martucciello, S..

3 recordsLinked to original sources

bioRxiv2026

Vegfr3 is required in the Tbx1 expression domain for cardiac outflow tract development.

Gene inactivation in model organisms has identified numerous genes and signaling pathways involved in mammalian cardiac OFT development. Human genetics data have implicated the VEGFR3 gene in OFT development but when and where it is required is unknown. In this study we determined the sensitivity of the developing murine cardiac OFT to reduced Vegfr3 gene dosage and we tested whether its requirement is dependent upon TBX1, a known regulator of Vegfr3 expression in cardiac and lymphatic endothelial cells. We found that in the mouse, a single copy if the Vegfr3 gene was sufficient for normal cardiac OFT development in most cases. Mutation of a single copy of the Tbx1 gene greatly enhanced the sensitivity of OFT development to Vegfr3 dosage reduction and led to the formation of severe OFT anomalies. In addition, deletion of Vegfr3 in the Tbx1 expression domain also led to OFT abnormalities. We used RNAscope to reveal the location of Vegfr3 and Tbx1 transcripts in midterm mouse embryos. This revealed co-localization of these transcripts that was restricted to the aortic sac endothelium, suggesting that the distal OFT is a potential site of genetic interaction between Vegfr3 and TBX1 that is critical for normal OFT development.

developmental biology↗

bioRxiv2022

VEGFR3 modulates brain microvessel branching in a mouse model of 22q11.2 deletion syndrome

The loss of a single copy of TBX1 accounts for most of the clinical signs and symptoms of 22q11.2 deletion syndrome (22q11.2DS), a common genetic disorder that is characterized by multiple congenital anomalies and brain-related clinical problems, some of which likely have vascular origins. Tbx1 mutant mice have brain vascular anomalies, thus making them a useful model to gain insights into the brain disorders associated with the human disease. Here, we found that Tbx1 has a dynamic expression pattern in brain endothelial cells (ECs), including tip cells, during early vascularization, but it is not expressed in EC progenitors. Its main morphogenetic function in the brain is to regulate negatively filopodia biogenesis and vessel branching. Because of similar phenotypes reported for Vegfr3 loss of function, we pursued a mouse genetic approach to test TBX1-VEGFR3 interaction through gain and loss of function experiments. Vegfr3 is expressed in brain ECs with extensive overlap with Tbx1 expression. We demonstrate that inactivating Vegfr3 in the Tbx1 expression domain in a Tbx1 mutant background enhances vessel branching and filopodia formation to a greater extent than that observed in the individual mutants. Furthermore, using a mouse transgenic line, we show that increasing Vegfr3 expression in the Tbx1 expression domain fully rescued the vessel branching and filopodia phenotypes caused by Tbx1 loss of function. Similar results were obtained using an in vitro model of endothelial tubulogenesis. Overall, these results provide genetic evidence that Vegfr3 is a regulator of early vessel branching and filopodia formation in the brain, and is a likely critical effector of the brain vascular phenotype caused by Tbx1 loss of function.

developmental biology↗

bioRxiv2019

Tbx1 interacts genetically with Vegfr3 to regulate cardiac lymphangiogenesis in mice

The transcription factor TBX1 is the major gene implicated in 22q11.2 deletion syndrome. The complex clinical phenotype includes vascular anomalies and a recent report presented new cases of primary lymphedema in 22q11.2DS patients. We have previously shown that Tbx1 activates Vegfr3 gene expression in lymphatic endothelial cells and that this activation is critical for lymphatic vessel development in prenatal mice and for their survival post-natally. Using loss-of-function genetics and transgenesis, we show a strong genetic interaction between Tbx1 and Vegfr3 in cardiac lymphangiogenesis that causes cardiac lymphatic vessel anomalies in compound heterozygotes. Intriguingly, different aspects of the cardiac lymphatic phenotype were regulated independently by the two genes. Tbx1Cre-activated Vegfr3 transgene expression was able to rescue the morphological abnormalities in the cardiac lymphatic vessels of compound heterozygotes, but it did not rescue the severe cardiac lymphatic vessel hypoplasia observed in Tbx1 homozygotes. Moreover, our study revealed a differential sensitivity between the ventral and dorsal cardiac lymphatic networks to the effects of altered Tbx1 and Vegfr3 gene dosage. Overall, our study demonstrates that a fine dosage balance between Tbx1 and Vegfr3 is required to regulate the number and morphology of cardiac lymphatic vessels.

developmental biology↗