title: Loss of cerebral cavernous malformation 3 (Ccm3) in neuroglia leads to CCM and vascular pathology.
abstract: Communication between neural cells and the vasculature is integral to the proper development and later function of the central nervous system. A mechanistic understanding of the interactions between components of the neurovascular unit has implications for various disorders, including cerebral cavernous malformations (CCMs) in which focal vascular lesions form throughout the central nervous system. Loss of function mutations in three genes with proven endothelial cell autonomous roles, CCM1/krev1 interaction trapped gene 1, CCM2, and CCM3/programmed cell death 10, cause familial CCM. By using neural specific conditional mouse mutants, we show that Ccm3 has both neural cell autonomous and nonautonomous functions. Gfap- or Emx1-Cre-mediated Ccm3 neural deletion leads to increased proliferation, increased survival, and activation of astrocytes through cell autonomous mechanisms involving activated Akt signaling. In addition, loss of neural CCM3 results in a vascular phenotype characterized by diffusely dilated and simplified cerebral vasculature along with formation of multiple vascular lesions that closely resemble human cavernomas through cell nonautonomous mechanisms. RNA sequencing of the vascular lesions shows abundant expression of molecules involved in cytoskeletal remodeling, including protein kinase A and Rho-GTPase signaling. Our findings implicate neural cells in the pathogenesis of CCMs, showing the importance of this pathway in neural/vascular interactions within the neurovascular unit.
authors.affiliation: Department of Neurosurgery, Yale Program on Neurogenetics, Yale School of Medicine, New Haven, CT 06520, USA. angeliki.louvi@yale.edu
authors.forename: Angeliki
authors.initials: A
authors.lastname: Louvi
authors.forename: Leiling
authors.initials: L
authors.lastname: Chen
authors.forename: Aimee M
authors.initials: AM
authors.lastname: Two
authors.forename: Haifeng
authors.initials: H
authors.lastname: Zhang
authors.forename: Wang
authors.initials: W
authors.lastname: Min
authors.forename: Murat
authors.initials: M
authors.lastname: Günel
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001253:Astrocytes / Q000473:pathology; D001808:Blood Vessels / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D049109:Cell Proliferation; D002470:Cell Survival; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D020786:Hemangioma, Cavernous, Central Nervous System / Q000378:metabolism* / Q000473:pathology*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008818:Mice, Neurologic Mutants; D009457:Neuroglia / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D010641:Phenotype; D017423:Sequence Analysis, RNA
chemical_list: D051017:Apoptosis Regulatory Proteins; D005904:Glial Fibrillary Acidic Protein; D008565:Membrane Proteins