Untangling sporadic brain arteriovenous malformations: towards targeting the KRAS/MAPK pathway.

Brain arteriovenous malformations (AVMs) are vascular lesions characterized by abnormal connections between parenchymal arteries and veins, bypassing a capillary bed, and forming a nidus. Brain AVMs are consequential as they are prone to rupture and associated with significant morbidity. They can broadly be subdivided into hereditary vs.

YAP/TAZ signaling in allantois-derived cells is required for placental vascularization.

Normal placental development and angiogenesis are crucial for fetal growth and maternal health during pregnancy. However, molecular regulation of placental angiogenesis has been difficult to study due to a lack of specific genetic tools that isolate the placenta from the embryo and yolk sac. To address this gap in knowledge we recently developed mice in which Cre is expressed in allantois-derived cells, including placental endothelial and stromal cells.

Nuclear receptor corepressors non-canonically drive glucocorticoid receptor-dependent activation of hepatic gluconeogenesis.

Nuclear receptor corepressors (NCoRs) function in multiprotein complexes containing histone deacetylase 3 (HDAC3) to alter transcriptional output primarily through repressive chromatin remodelling at target loci. In the liver, loss of HDAC3 causes a marked hepatosteatosis largely because of de-repression of genes involved in lipid metabolism; however, the individual roles and contribution of other complex members to hepatic and systemic metabolic regulation are unclear. Here we show that adult loss of both NCoR1 and NCoR2 (double knockout (KO)) in hepatocytes phenocopied the hepatomegalic fatty liver phenotype of HDAC3 KO.

Cell-autonomous requirement for ACE2 across organs in lethal mouse SARS-CoV-2 infection.

Angiotensin-converting enzyme 2 (ACE2) is the cell-surface receptor for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). While its central role in Coronavirus Disease 2019 (COVID-19) pathogenesis is indisputable, there remains significant debate regarding the role of this transmembrane carboxypeptidase in the disease course. These include the role of soluble versus membrane-bound ACE2, as well as ACE2-independent mechanisms that may contribute to viral spread.

FZD2 Regulates Murine Hair Follicle Function and Maintenance.

Fzd2 is required for hair follicle function and maintenance in mice.

SARS-CoV-2 infection of olfactory epithelial cells and neurons drives acute lung injury and lethal COVID-19 in mice.

Lethal COVID-19 is associated with respiratory failure that is thought to be caused by acute respiratory distress syndrome (ARDS) secondary to pulmonary infection. To date, the cellular pathogenesis has been inferred from studies describing the expression of ACE2, a transmembrane protein required for SARS-CoV-2 infection, and detection of viral RNA or protein in infected humans, model animals, and cultured cells. To functionally test the cellular mechanisms of COVID-19, we generated animals in which human ACE2 (hACE2) is expressed from the mouse locus in a manner that permits cell-specific, Cre-mediated loss of function.

Overexpression of Desmoglein 2 in a Mouse Model of Gorlin Syndrome Enhances Spontaneous Basal Cell Carcinoma Formation through STAT3-Mediated Gli1 Expression.

Activation of the hedgehog pathway is causative of virtually all sporadic and Gorlin syndrome-related basal cell carcinomas (BCCs), with loss of function of Ptc1 being the most common genomic lesion. Sporadic BCCs also overexpress Dsg2, a desmosomal cadherin normally found in the basal layer. Using a mouse model of Gorlin syndrome (Ptc1 mice), we found that overexpressing Dsg2 in the basal layer (K14-Dsg2/Ptc1 mice) or the superficial epidermis (Inv-Dsg2/Ptc1 mice) resulted in increased spontaneous BCC formation at 3 and 6 months, respectively.