Friedreich ataxia (FRDA) is a neurodegenerative disorder caused by an unstable GAA repeat expansion mutation within intron 1 of the FXN gene. However, the origins of the GAA repeat expansion, its unstable dynamics within different cells and tissues, and its effects on frataxin expression are not yet completely understood. Therefore, we have chosen to generate representative FRDA mouse models by using the human FXN GAA repeat expansion itself as the genetically modified mutation. We have previously reported the establishment of two lines of human FXN YAC transgenic mice that contain unstable GAA repeat expansions within the appropriate genomic context. We now describe the generation of FRDA mouse models by crossbreeding of both lines of human FXN YAC transgenic mice with heterozygous Fxn knockout mice. The resultant FRDA mice that express only human-derived frataxin show comparatively reduced levels of frataxin mRNA and protein expression, decreased aconitase activity, and oxidative stress, leading to progressive neurodegenerative and cardiac pathological phenotypes. Coordination deficits are present, as measured by accelerating rotarod analysis, together with a progressive decrease in locomotor activity and increase in weight. Large vacuoles are detected within neurons of the dorsal root ganglia (DRG), predominantly within the lumbar regions in 6-month-old mice, but spreading to the cervical regions after 1 year of age. Secondary demyelination of large axons is also detected within the lumbar roots of older mice. Lipofuscin deposition is increased in both DRG neurons and cardiomyocytes, and iron deposition is detected in cardiomyocytes after 1 year of age. These mice represent the first GAA repeat expansion-based FRDA mouse models that exhibit progressive FRDA-like pathology and thus will be of use in testing potential therapeutic strategies, particularly GAA repeat-based strategies.

Machado-Joseph disease (MJD; MIM 109150) is a late-onset neurodegenerative disorder caused by the expansion of a polyglutamine tract within the MJD1 gene. We have previously reported the generation of human yeast artificial chromosome (YAC) constructs encompassing the MJD1 locus into which expanded (CAG)(76) and (CAG)(84) repeat motifs have been introduced by homologous recombination. Transgenic mice containing pathological alleles with polyglutamine tract lengths of 64, 67, 72, 76 and 84 repeats, as well as the wild type with 15 repeats, have now been generated using these YAC constructs. The mice with expanded alleles demonstrate a mild and slowly progressive cerebellar deficit, manifesting as early as 4 weeks of age. As the disease progresses, pelvic elevation becomes markedly flattened, accompanied by hypotonia, and motor and sensory loss. Neuronal intranuclear inclusion (NII) formation and cell loss is prominent in the pontine and dentate nuclei, with variable cell loss in other regions of the cerebellum from 4 weeks of age. Interestingly, peripheral nerve demyelination and axonal loss is detected in symptomatic mice from 26 weeks of age. In contrast, transgenic mice carrying the wild-type (CAG)(15) allele of the MJD1 locus appear completely normal at 20 months. Disease severity increases with the level of expression of the expanded protein and the size of the repeat. These mice are representative of MJD and will be a valuable resource for the detailed analysis of the roles of repeat length, tissue specificity and level of expression in the neurodegenerative processes underlying MJD pathogenesis.

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Endothelial interactions with the extracellular matrix (ECM) play important roles in angiogenesis but whether specific ECM signals can determine specific cellular morphologies is unclear. The authors compared in vitro ECM-induced morphological responses of the phenotypically distinct human placental microvascular endothelial cells (HPMECs) with large vessel endothelial cells (HUVECs). HPMECs showed distinct patterns of reorganization in response to collagen-I or collagen-IV (monolayer disruption, sprouting, migration) and Matrigel or laminin-A (intussusception, cord formation, tubulogenesis), and an intermediate response to fibrin; whereas HUVECs responded similarly to collagen-1 and Matrigel (elongation, lattice formation, vacuolation) and showed little response to fibrin. Although the extent of collagen and Matrigel responses of HPMECs were increased by serum, acidic or basic fibroblast growth factor (aFGF, bFGF), or vascular endothelial growth factor (VEGF), and varied with matrix protein concentration, the basic patterns were matrix specific, and were independent of fibronectin. The collagen responses correlated with disruption of adherens and tight junctions and the formation of filopodial protrusions. Matrigel responses were associated with up-regulated junctional localization of VE-cadherin, and tubulogenesis developed mainly through paracellular remodeling rather than intracellular vacuolation. Overall, these findings suggest that distinct ECM interactions stimulate specific morphological responses. These signals may regulate morphological behaviour in the angiogenesis cycle, switching endothelial cells between migratory and vasculogenic phenotypes.