Ccm3, a gene associated with cerebral cavernous malformations, is required for neuronal migration

Abstract

Loss of function of cerebral cavernous malformation 3 (CCM3) results in an autosomal dominant cerebrovascular disorder. Here, we uncover a developmental role for CCM3 in regulating neuronal migration in the neocortex. Using cell type-specific gene inactivation in mice, we show that CCM3 has both cell autonomous and cell nonautonomous functions in neural progenitors and is specifically required in radial glia and newly born pyramidal neurons migrating through the subventricular zone, but not in those migrating through the cortical plate. Loss of CCM3 function leads to RhoA activation, alterations in the actin and microtubule cytoskeleton affecting neuronal morphology, and abnormalities in laminar positioning of primarily late-born neurons, indicating CCM3 involvement in radial glia-dependent locomotion and possible interaction with the Cdk5/RhoA pathway. Thus, we identify a novel cytoplasmic regulator of neuronal migration and demonstrate that its inactivation in radial glia progenitors and nascent neurons produces severe malformations of cortical development.

Cerebral Cavernous Malformations: Review of the Genetic and Protein–Protein Interactions Resulting in Disease Pathogenesis

“…Patients with PDCD10 mutations had an increased number of lesions and also presented with lesion hemorrhages earlier in life. Moreover, these authors found additional PDCD10 aberrations in addition to the CCMs, including scoliosis, cognitive disability, and skin lesions, further suggesting that PDCD10 plays other roles in tissue development aside from endothelial cell formation (43, 44). …”

“…Louvi et al discovered that PDCD10 has a pivotal role in neuronal migration via suppression of RhoA signaling. They demonstrated that PDCD10 activity is required for proper radial glia and pyramidal neuron migration through the subventricular zone (43). Loss of PDCD10 resulted in dysregulation of the actin and microtubule cytoskeleton and adversely affected cellular morphology and migration.…”

Molecular and Genetic Basis of Cerebral Cavernous Malformations

“…CCM3 geninin knock-out (ortadan kaldırılması) edilmesine dayalı çalışmalarda, kortikal tabakalanmalarda incelmelerin olduğu ve bu durumun yetişkin farelerde de devam ettiği belirlenmiştir. In vitro ve in vivo çalışmaların sonuçları, günümüzde CCM3'ün nöronal morfolojiyi etkileyebileceğini söylememize imkân sağlamaktadır (38).…”

Combined HMG-COA reductase and prenylation inhibition in treatment of CCM

“…Treatment options include observation of asymptomatic lesions, antiepileptic medication, and surgical excision of lesions in patients with symptomatic or repetitive hemorrhages or intractable seizures; however pharmacological therapies that improve outcome are lacking. CCM disease is usually sporadic, although 20% of patients carry lossof-function mutations in one of three genes: CCM1 (also known as "KRIT1"), CCM2, and CCM3 (also known as "PDCD10") (3), which encode structurally unrelated cytoplasmic proteins with critical roles in endothelial cells (4) and, uniquely for CCM3, in neurons and astrocytes as well (5,6). CCM3 loss in neural progenitors results in hyperproliferation/activation of brain astrocytes and enhanced activity of RhoA in vivo and increased proliferation and survival of primary astrocytes in vitro (5,6).…”

“…CCM disease is usually sporadic, although 20% of patients carry lossof-function mutations in one of three genes: CCM1 (also known as "KRIT1"), CCM2, and CCM3 (also known as "PDCD10") (3), which encode structurally unrelated cytoplasmic proteins with critical roles in endothelial cells (4) and, uniquely for CCM3, in neurons and astrocytes as well (5,6). CCM3 loss in neural progenitors results in hyperproliferation/activation of brain astrocytes and enhanced activity of RhoA in vivo and increased proliferation and survival of primary astrocytes in vitro (5,6). We took advantage of these well-defined cellular phenotypes of CCM3 loss to explore potential pharmacological treatment options for CCM.…”