The transcription factor COUP-TFI is required for hippocampal development and dentate granules neurogenesis

The archicortex, and in particular the hippocampus, integrates a wide range of signals through a particular laminar organization in which controlled expression of different transcription factors plays a major role during development. The nuclear receptor COUP-TFI is involved in many aspects of cortical neurogenesis, from arealization to cell-type specification and axon formation. Interestingly, COUP-TFI is expressed in a graded rostro-caudal manner in the hippocampus, with high levels in the neuroepithelium of the dentate gyrus (DG) and in the mature granule cell layer. To assess its role in hippocampal development, two independent conditional lines, in which COUP-TFI is either inactivated in all cortical progenitors or exclusively in post-mitotic neurons, were used. While absence of COUP-TFI function in post-mitotic neurons has a minor effect on the overall hippocampal development, loss-of-function of COUP-TFI in cortical progenitors leads to dramatic malformations in the growth and maturation of the hippocampus and dentate gyrus. In particular, the temporal progression of granule cell differentiation is affected resulting ultimately in decreased adult neurogenesis in adult COUP-TFI mutant mice. Furthermore, various components of the Notch-Delta signaling pathway required for the different steps of granule differentiation are altered, leading to an abnormal distribution of progenitors and immature granule cells during development of the dentate gyrus. Altogether, these results indicate that COUP-TFI plays an essential role in regulating particular aspects of dentate granule cell neurogenesis, and, importantly, propose COUP-TFI as a novel factor required in maintaining the adult neuronal stem cell niche

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, a common genetic disorder that is characterized by multiple congenital anom-alies 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 human disease. Here, we found that the main morphogenetic function of TBX1 in the mouse brain is to suppress vessel branching morphogenesis through regulation of Vegfr3. We demonstrate that inactivating Vegfr3 in the Tbx1 expression domain on a Tbx1 mutant background enhances brain vessel branching and filopodia formation, whereas increasing Vegfr3 expression in this domain fully rescued these phenotypes. Similar results were obtained using an in vitro model of endothelial tubu-logenesis. Overall, the results of this study provide genetic evidence that VEGFR3 is a regulator of early vessel branching and filopodia formation in the mouse brain and is a likely mediator of the brain vascular phenotype caused by Tbx1 loss of function

Mid-Term Outcome of Ventricular Arrhythmias Catheter Ablation in Patients with Chronic Coronary Total Occlusion Compared to Ischemic and Non-Ischemic Patients

Chronic coronary total occlusions (CTO) are considered an emerging predictor of ventricular arrhythmias (VAs), but currently there are few data on arrhythmic outcomes in patients affected by CTO undergoing radiofrequency catheter ablation of VAs. This study sought to evaluate the impact of unrevascularized CTO on the recurrence of VAs after catheter ablation. This was a single-center retrospective study enrolling 120 patients between 2015 and 2020. All patients were admitted for ventricular tachycardia (VT) or high premature ventricular contractions burden (>25% detected by Holter ECG), without evidence of acute coronary syndrome; they underwent coronary angiography, electrophysiology (EP) study, and three-dimensional electroanatomic mapping (3D-EAM) followed by VAs ablation. Twenty-eight patients (23%) of 120 patients showed CTO at coronary angiography. At baseline, the CTO group presented with higher prevalence of hypertension, chronic renal disease, systolic ventricular dysfunction, secondary prevention ICD implantation, and higher rate of LAVA by 3D-EAM compared with the non-CTO group. At a median follow-up of 15 months (range 1-96 months) after catheter ablation, the only independent predictor of VAs recurrence was the presence of moderate to severe left ventricular (LV) dysfunction. Therefore, the presence of CTO does not predict VAs recurrence after catheter ablation, which is instead predicted by LV dysfunction

Mid-Term Outcome of Ventricular Arrhythmias Catheter Ablation in Patients with Chronic Coronary Total Occlusion Compared to Ischemic and Non-Ischemic Patients

Chronic coronary total occlusions (CTO) are considered an emerging predictor of ventricular arrhythmias (VAs), but currently there are few data on arrhythmic outcomes in patients affected by CTO undergoing radiofrequency catheter ablation of VAs. This study sought to evaluate the impact of unrevascularized CTO on the recurrence of VAs after catheter ablation. This was a single-center retrospective study enrolling 120 patients between 2015 and 2020. All patients were admitted for ventricular tachycardia (VT) or high premature ventricular contractions burden (>25% detected by Holter ECG), without evidence of acute coronary syndrome; they underwent coronary angiography, electrophysiology (EP) study, and three-dimensional electroanatomic mapping (3D-EAM) followed by VAs ablation. Twenty-eight patients (23%) of 120 patients showed CTO at coronary angiography. At baseline, the CTO group presented with higher prevalence of hypertension, chronic renal disease, systolic ventricular dysfunction, secondary prevention ICD implantation, and higher rate of LAVA by 3D-EAM compared with the non-CTO group. At a median follow-up of 15 months (range 1–96 months) after catheter ablation, the only independent predictor of VAs recurrence was the presence of moderate to severe left ventricular (LV) dysfunction. Therefore, the presence of CTO does not predict VAs recurrence after catheter ablation, which is instead predicted by LV dysfunction

A phenotypic rescue approach identifies lineage regionalization defects in a mouse model of DiGeorge syndrome

TBX1 is a key regulator of pharyngeal apparatus (PhAp) development. Vitamin B12 (vB12) treatment partially rescues aortic arch patterning defects of Tbx1(+/−) embryos. Here, we show that it also improves cardiac outflow tract septation and branchiomeric muscle anomalies of Tbx1 hypomorphic mutants. At the molecular level, in vivo vB12 treatment enabled us to identify genes that were dysregulated by Tbx1 haploinsufficiency and rescued by treatment. We found that SNAI2, also known as SLUG, encoded by the rescued gene Snai2, identified a population of mesodermal cells that was partially overlapping with, but distinct from, ISL1(+) and TBX1(+) populations. In addition, SNAI2(+) cells were mislocalized and had a greater tendency to aggregate in Tbx1(+/−) and Tbx1(−/−) embryos, and vB12 treatment restored cellular distribution. Adjacent neural crest-derived mesenchymal cells, which do not express TBX1, were also affected, showing enhanced segregation from cardiopharyngeal mesodermal cells. We propose that TBX1 regulates cell distribution in the core mesoderm and the arrangement of multiple lineages within the PhAp