PDCD10, THE GENE MUTATED IN CEREBRAL CAVERNOUS MALFORMATION 3, IS EXPRESSED IN THE NEUROVASCULAR UNIT

OBJECTIVEMutations in the programmed cell death 10 gene, PDCD10, cause the autosomal-dominant familial cerebral cavernous malformation 3 (CCM3). Little is known about the function of this gene in disease pathogenesis. METHODSAs a first step, we analyzed the messenger ribonucleic acid (mRNA) expression of CCM3 in the embryonic and postnatal mouse brain by in situ hybridization. We generated and characterized CCM3-specific polyclonal antibodies and analyzed CCM3 protein expression in human cerebral and solid organ (extracerebral) tissues using immunohistochemistry. RESULTSIn embryonic mouse brain, CCM3 mRNA is seen in the ventricular, subventricular, and intermediate zones, the cortical plate, the developing septum, striatum, midbrain, pons, cerebellum, and medulla. In the postnatal mouse brain, we detected CCM3/PDCD10 expression in the olfactory bulb, neocortex, striatum, septal nuclei, hippocampus, dentate gyrus, thalamic and hypothalamic nuclei, inferior colliculus, Purkinje and granule cell layers and deep nuclei of the cerebellum, and in many cells and nuclei in the medulla. Similar to CCM1 and CCM2, the CCM3/PDCD10 protein is expressed in the neurovascular unit but weakly in venous structures within cortical, subcortical, and brainstem tissue. CCM3/PDCD10 protein is strongly expressed in arterial endothelium but weakly or not at all in venous endothelium of extracerebral tissue. CONCLUSIONThe expression pattern of CCM3/PDCD10 in multiple organ systems displays similarities to CCM1 and CCM2. PDCD10/CCM3 is highly expressed in the neurovascular unit and in the arterial endothelium of structures within multiple organ systems, including the brain. These data provide additional information about CCM3 expression and its role in lesion development and pathogenesis.

[1]  U. Felbor,et al.  CCM3 interacts with CCM2 indicating common pathogenesis for cerebral cavernous malformations , 2007, Neurogenetics.

[2]  H. Dietz,et al.  INTERACTION BETWEEN KRIT1 AND MALCAVERNIN: IMPLICATIONS FOR THE PATHOGENESIS OF CEREBRAL CAVERNOUS MALFORMATIONS , 2007, Neurosurgery.

[3]  N. Petit,et al.  Patterns of expression of the three cerebral cavernous malformation (CCM) genes during embryonic and postnatal brain development. , 2006, Gene expression patterns : GEP.

[4]  A. Louvi,et al.  CCM2 expression parallels that of CCM1. , 2006, Stroke.

[5]  C. Liquori,et al.  Low frequency of PDCD10 mutations in a panel of CCM3 probands: potential for a fourth CCM locus , 2006, Human mutation.

[6]  H. Matsunami,et al.  Neuronal expression of the Ccm2 gene in a new mouse model of cerebral cavernous malformations , 2006, Mammalian Genome.

[7]  C. Elger,et al.  CCM3 mutations are uncommon in cerebral cavernous malformations , 2005, Neurology.

[8]  B. O’Roak,et al.  Mutations in Apoptosis-related Gene, PDCD10, Cause Cerebral Cavernous Malformation 3 , 2005, Neurosurgery.

[9]  D. Marchuk,et al.  CCM1 and CCM2 protein interactions in cell signaling: implications for cerebral cavernous malformations pathogenesis. , 2005, Human molecular genetics.

[10]  M. Clanet,et al.  Mutations within the programmed cell death 10 gene cause cerebral cavernous malformations. , 2005, American journal of human genetics.

[11]  Murat Gunel,et al.  Krev1 interaction trapped-1/cerebral cavernous malformation-1 protein expression during early angiogenesis. , 2004, Journal of neurosurgery.

[12]  R. Lifton,et al.  KRIT1/Cerebral Cavernous Malformation 1 Protein Localizes to Vascular Endothelium, Astrocytes, and Pyramidal Cells of the Adult Human Cerebral Cortex , 2004, Neurosurgery.

[13]  C. Liquori,et al.  Mutations in a gene encoding a novel protein containing a phosphotyrosine-binding domain cause type 2 cerebral cavernous malformations. , 2003, American journal of human genetics.

[14]  M. Dell'Acqua,et al.  Rac–MEKK3–MKK3 scaffolding for p38 MAPK activation during hyperosmotic shock , 2003, Nature Cell Biology.

[15]  Johnson,et al.  Mutational analysis of 206 families with cavernous malformations. , 2003, Journal of neurosurgery.

[16]  D. Ledbetter,et al.  14-3-3ε is important for neuronal migration by binding to NUDEL: a molecular explanation for Miller–Dieker syndrome , 2003, Nature Genetics.

[17]  F. Chapon,et al.  Krit1/cerebral cavernous malformation 1 mRNA is preferentially expressed in neurons and epithelial cells in embryo and adult , 2002, Mechanisms of Development.

[18]  R. Lifton,et al.  KRIT1, a gene mutated in cerebral cavernous malformation, encodes a microtubule-associated protein , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[19]  Erica A Golemis,et al.  KRIT1 association with the integrin-binding protein ICAP-1: a new direction in the elucidation of cerebral cavernous malformations (CCM1) pathogenesis. , 2002, Human molecular genetics.

[20]  D. Chang,et al.  Interaction between krit1 and icap1alpha infers perturbation of integrin beta1-mediated angiogenesis in the pathogenesis of cerebral cavernous malformation. , 2001, Human molecular genetics.

[21]  B. Crain,et al.  Ultrastructural and immunocytochemical evidence that an incompetent blood-brain barrier is related to the pathophysiology of cavernous malformations , 2001, Journal of neurology, neurosurgery, and psychiatry.

[22]  A. Joutel,et al.  Truncating mutations in CCM1, encoding KRIT1, cause hereditary cavernous angiomas , 1999, Nature Genetics.

[23]  R. Scott,et al.  Multilocus linkage identifies two new loci for a mendelian form of stroke, cerebral cavernous malformation, at 7p15-13 and 3q25.2-27. , 1998, Human molecular genetics.

[24]  D. Ledbetter,et al.  Graded reduction of Pafah1b1 (Lis1) activity results in neuronal migration defects and early embryonic lethality , 1998, Nature Genetics.

[25]  I. Awad,et al.  Genetic heterogeneity of inherited cerebral cavernous malformation. , 1996, Neurosurgery.

[26]  L. Morrison,et al.  A founder mutation as a cause of cerebral cavernous malformation in Hispanic Americans. , 1996, The New England journal of medicine.

[27]  J. Weber,et al.  Refined localization of the cerebral cavernous malformation gene (CCM1) to a 4-cM interval of chromosome 7q contained in a well-defined YAC contig. , 1995, Genome research.

[28]  J. Weber,et al.  A gene responsible for cavernous malformations of the brain maps to chromosome 7q. , 1995, Human molecular genetics.

[29]  S. Tole,et al.  Regionalization of the developing forebrain: a comparison of FORSE-1, Dlx-2, and BF-1 , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.