Gain of MEKK3 signalling is shown to cause cerebral cavernous malformations (CCMs) via activation of the target genes Klf2 and Klf4; endothelial-specific loss of MEKK3, KLF2 or KLF4 prevents lesion formation and lethality in a mouse CCM model. Mark Kahn and colleagues identify a causal mechanism for the development of cerebral cavernous malformations (CCMs) — vascular malformations that cause stroke and seizures. The CCM complex is known to regulate MEKK3 during heart development. Here the authors show that gain of MEKK3 signalling is causal to CCM development via activating the MEKK3 target genes Klf2 and Klf4. Endothelial-specific loss of MEKK3, KLF2 or KLF4 rescues lethality in a mouse CCM model. Cerebral cavernous malformations (CCMs) are common inherited and sporadic vascular malformations that cause strokes and seizures in younger individuals1. CCMs arise from endothelial cell loss of KRIT1, CCM2 or PDCD10, non-homologous proteins that form an adaptor complex2. How disruption of the CCM complex results in disease remains controversial, with numerous signalling pathways (including Rho3,4, SMAD5 and Wnt/β-catenin6) and processes such as endothelial–mesenchymal transition (EndMT)5 proposed to have causal roles. CCM2 binds to MEKK3 (refs 7, 8, 9, 10, 11), and we have recently shown that CCM complex regulation of MEKK3 is essential during vertebrate heart development12. Here we investigate this mechanism in CCM disease pathogenesis. Using a neonatal mouse model of CCM disease, we show that expression of the MEKK3 target genes Klf2 and Klf4, as well as Rho and ADAMTS protease activity, are increased in the endothelial cells of early CCM lesions. By contrast, we find no evidence of EndMT or increased SMAD or Wnt signalling during early CCM formation. Endothelial-specific loss of Map3k3 (also known as Mekk3), Klf2 or Klf4 markedly prevents lesion formation, reverses the increase in Rho activity, and rescues lethality. Consistent with these findings in mice, we show that endothelial expression of KLF2 and KLF4 is increased in human familial and sporadic CCM lesions, and that a disease-causing human CCM2 mutation abrogates the MEKK3 interaction without affecting CCM complex formation. These studies identify gain of MEKK3 signalling and KLF2/4 function as causal mechanisms for CCM pathogenesis that may be targeted to develop new CCM therapeutics.

Cerebral cavernous malformation (CCM) is a common cerebrovascular disease that can occur sporadically or be inherited. They are major causes of stroke, cerebral hemorrhage, and neurological deficits in the younger population. Loss-of-function mutations in three genes, CCM1, CCM2, and CCM3, have been identified as the cause of human CCMs. Currently, no drug is available to treat CCM disease. Hyperactive mitogen-activated protein kinase kinase Kinase 3 (MEKK3) kinase signaling as a consequence of loss of CCM genes is an underlying cause of CCM lesion development. Using a U.S. Food and Drug Administration–approved kinase inhibitor library combined with virtual modeling and biochemical and cellular assays, we have identified a clinically approved small compound, ponatinib, that is capable of inhibiting MEKK3 activity and normalizing expression of downstream kruppel-like factor (KLF) target genes. Treatment with this compound in neonatal mouse models of CCM can prevent the formation of new CCM lesions and reduce the growth of already formed lesions. At the ultracellular level, ponatinib can normalize the flattening and disorganization of the endothelium caused by CCM deficiency. Collectively, our study demonstrates ponatinib as a novel compound that may prevent CCM initiation and progression in mouse models through inhibition of MEKK3-KLF signaling.

Luminescence properties of vertically aligned, crystalline ZnO nanorods are studied by cathodoluminescence (CL) spectroscopy and microscopy. Results show that luminescence characteristics vary dramatically with location on the nanorod as well as CL excitation depth. CL inhomogeneity is observed between the nanorod tip and sidewalls, accompanied by a variation in the chemical environment of surface oxygen ions as probed by photoemission spectroscopy. Our findings demonstrate that CL can provide useful information on the local optical properties of nanostructured materials, which is simply beyond the capability of other methods.