Conditional N-rasG12V expression promotes manifestations of neurofibromatosis in a mouse model

Abstract

Human clinical neurofibromatosis type 1 (NF1) and type 2 (NF2) result from mutations and inactivation of neurofibromin and merlin genes, respectively, which negatively regulate Ras pathways. To evaluate the contribution of N-Ras activity to the development of NF, we generated a novel transgenic mouse expressing oncogenic N-ras specifically in central nerve cells, neural crest-derived cells and lens epithelial cells. Soon after birth, the mouse skin showed hyperpigmentation of the epidermis and melanin-laden macrophages in the dermis, as observed in the cafe´-au-lait spots of human cases. At 3 months of age, all the mice had neurofibromas in the skin and neurofibroma-like tumors with structure similar to WagnerMeissner bodies in the adrenal medulla. At 4 months of age, all the mice developed subcapsular cataract. In the 5th month, some developed protruding dermal neurofibromas involving subcutaneous fat. However, plexiform neurofibroma, schwannoma, astrocytoma and pheochromocytoma were not observed in the mice, suggesting a requirement for signal(s) other than the activated N-Ras pathway to induce these tumors. Thus, the activated N-Ras signal may be a main pathway for the development of the disease phenotypes characteristic of NF.

Camk2a-Cre-mediated conditional deletion of chromatin remodeler Brg1 causes perinatal hydrocephalus

“…Using a more sensitive reporter, we showed Camk2a-Cre activities begin at late embryonic stage and Camk2a-Cre mediated Brg1 deletion led to perinatal hydrocephalus. Notably, another Camk2a-Cre line also has activity during embryonic stages [21]. The hydrocephalus phenotype is unique to the Camk2a-Cre Brg1 F/F mice and caused by Camk2a-mediated Brg1 deletion since mice of the parental strains ( Camk2a-Cre Brg1 F/+ miceand Brg1 F/F mice) had normal brain structures.…”

PTEN dosage is essential for neurofibroma development and malignant transformation

“…Furthermore, the learning deficits in Nf1 ϩ/Ϫ mice can be rescued by decreasing RAS function either genetically (crossing with the K-Ras ϩ/Ϫ heterozygote) or pharmacologically (treated with farnesyltransferase inhibitors of Ras) (37,39). Although mice with oncogenic N-Ras expression in nerve and neural crest-derived cells mimic two main symptoms of human NF1 and/or NF2, namely pigmentary abnormality and dermal NFs, plexiform NF, Schwannoma, astrocytoma, and pheochromocytoma were not detected (40). Since the three forms of Ras, (H, K, N) are expressed in different cells, this could explain the absence of some of these tumor types in our model and the presence of various other tumors.…”

Atlas of transgenic Tet-Off Ca2+/calmodulin-dependent protein kinase II and prion protein promoter activity in the mouse brain

“…The PrP promoter line has been successfully used in several studies of various diseases, including prion diseases (Safar et al, 2005;Tremblay et al, 1998), Parkinson's disease (Nuber et al, 2008), analysis of alcohol consumption (Choi et al, 2002), spinocerebellar ataxia type 3 (Boy et al, 2009), and neurofilament transport (Millecamps et al, 2007). The CamKII promoter line has been used for the investigation of synaptic plasticity, learning and memory consolidation (Bukalo et al, 2004;Limback-Stokin et al, 2004;Mayford et al, 1997;Wood et al, 2005), neurodevelopmental disorders (Alvarez-Saavedra et al, 2007;Jerecic et al, 2001), and for the generation of transgenic mouse models for Alzheimer's disease (Jankowsky et al, 2005), Huntington's disease (Yamamoto et al, 2000), Parkinson's disease (Nuber et al, 2008), neocortical degeneration (Muyllaert et al, 2008), schizophrenia (Pletnikov et al, 2008), and neurofibromatosis (Saito et al, 2007).…”