In addition to controlling a switch to glycolytic metabolism and induction of erythropoiesis and angiogenesis, hypoxia promotes the undifferentiated cell state in various stem and precursor cell populations. Here, we show that the latter process requires Notch signaling. Hypoxia blocks neuronal and myogenic differentiation in a Notch-dependent manner. Hypoxia activates Notch-responsive promoters and increases expression of Notch direct downstream genes. The Notch intracellular domain interacts with HIF-1alpha, a global regulator of oxygen homeostasis, and HIF-1alpha is recruited to Notch-responsive promoters upon Notch activation under hypoxic conditions. Taken together, these data provide molecular insights into how reduced oxygen levels control the cellular differentiation status and demonstrate a role for Notch in this process.

Tumor hypoxia is linked to increased metastatic potential, but the molecular mechanisms coupling hypoxia to metastasis are poorly understood. Here, we show that Notch signaling is required to convert the hypoxic stimulus into epithelial-mesenchymal transition (EMT), increased motility, and invasiveness. Inhibition of Notch signaling abrogated hypoxia-induced EMT and invasion, and, conversely, an activated form of Notch could substitute for hypoxia to induce these processes. Notch signaling deploys two distinct mechanisms that act in synergy to control the expression of Snail-1, a critical regulator of EMT.

Human MIEF1 recruits Drp1 to mitochondrial outer membranes and promotes mitochondrial fusion rather than fissionMitochondrial morphology depends on the balance between fission and fusion events. This study identifies a receptor for the fission factor Drp1 within the mitochondrial outer membrane, which inhibits Drp1-mediated fission and activates fusion.

Abstract-Notch signaling is critically important for proper architecture of the vascular system, and mutations in NOTCH3 are associated with CADASIL, a stroke and dementia syndrome with vascular smooth muscle cell (VSMC) dysfunction.In this report, we link Notch signaling to platelet-derived growth factor (PDGF) signaling, a key determinant of VSMC biology, and show that PDGF receptor (PDGFR)-␤ is a novel immediate Notch target gene. PDGFR-␤ expression was upregulated by Notch ligand induction or by activated forms of the Notch receptor. Moreover, upregulation of PDGFR-␤ expression in response to Notch activation critically required the Notch signal integrator CSL. In primary VSMCs, PDGFR-␤ expression was robustly upregulated by Notch signaling, leading to an augmented intracellular response to PDGF stimulation. In newborn Notch3-deficient mice, PDGFR-␤ expression was strongly reduced in the VSMCs that later develop an aberrant morphology. In keeping with this, PDGFR-␤ upregulation in response to Notch activation was reduced also in Notch3-deficient embryonic stem cells. Finally, in VSMCs from a CADASIL patient carrying a NOTCH3 missense mutation, upregulation of PDGFR-␤ mRNA and protein in response to ligand-induced Notch activation was significantly reduced. In sum, these data reveal a hierarchy for 2 important signaling systems, Notch and PDGF, in the vasculature and provide insights into how dysregulated Notch signaling perturbs VSMC differentiation and function. Key Words: PDGF Ⅲ VSMC Ⅲ CADASIL Ⅲ vasculogenesis Ⅲ angiogenesis T he vasculature is formed by an initial aggregation of angioblasts during vasculogenesis, followed by remodeling of the primitive vascular plexus through angiogenesis. 1,2 Recruitment of mural cells, which differentiate to vascular smooth muscle cells (VSMCs) and pericytes, to the endothelial tube is required for stabilization of the vessels. 3 Endothelial and mural cell differentiation is controlled by several key signaling pathways, including PDGF and Notch signaling, 2 and, in this study, we addressed the interrelationship between Notch and PDGF signaling in VSMCs.PDGF signaling is critical for several steps in vascular development and for the homeostasis of blood vessels. There are 4 different genes encoding PDGF ligands (PDGFA through -D), and 2 genes encoding PDGF receptors (PDGFRs) (PDGFR-␣ and -␤). PDGFRs are receptor tyrosine kinases that, on interaction with ligand, activate several intracellular signaling pathways, including phosphatidylinositol 3-kinase and mitogen-activated protein kinase signaling. 4 Loss-of-function analysis has revealed the importance for PDGF-BB/ PDGFR-␤ signaling in vascular development. Mice in which the PDGF-B or PDGFR-␤ gene has been targeted are embryonic lethal, and the phenotypes support a model where endothelial cells, through secretion of PDGF-BB, stimulate proliferation and recruitment of PDGFR-␤ positive mural cells during embryonic development. 5,6 PDGF signaling plays an important role also in restenosis in response to angioplasty. 7 N...