Biology subjects

Flore, G.

Publications and source records attributed to Flore, G..

2 recordsLinked to original sources

bioRxiv2024

Tbx1 haploinsufficiency causes brain metabolic and behavioral anomalies in adult mice which are corrected by vitamin B12 treatment

IntroductionThe brain-related phenotypes observed in 22q11.2 deletion syndrome (22q11.2DS) are highly variable and their origin is poorly understood. Changes in brain metabolism may cause or contribute to the phenotypes, given that many of the deleted genes (approx. 10%) are implicated in metabolic processes, but this is currently unknown. It is clearly important to address this knowledge gap, but in humans, the primary material required for studying brain metabolism is inaccessible. For this reason, we sought to address the issue using two mouse models of 22q11.2DS. MethodsWe used three independent approaches to investigate brain metabolism in young adult mice, namely, mass spectrometry, nuclear magnetic resonance spectroscopy and transcriptomics. We selected to study primarily Tbx1 single gene mutants because it is the primary candidate disease gene. We then confirmed key findings in the multi-gene deletion mutant Df1/+. ResultsWe found that Tbx1 mutants have alterations of specific brain metabolites, including methylmalonic acid, which is highly brain-toxic, as well as a more general metabolomic imbalance. We provide transcriptomic evidence of an interaction genotype-vB12 treatment, and behavioural evidence of a response to vB12 treatment, which rescued some of the behavioural anomaly observed in Tbx1 mutants. We conclude that Tbx1 haploinsufficiency causes extensive brain metabolic anomalies, which are partially responsive to vB12 treatment. We suggest that alterations of glutamine-glutamate metabolism and fatty acid metabolism are key components of the metabolic phenotype in these mutants.

genetics↗

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↗