NXF, a member of the basic helix-loop-helix-PAS transcription factor family, is thought to be involved in functional regulation of neurons, because significant expression is found in the mature brain. To elucidate functions of NXF in vivo, here we generated mice lacking NXF using homologous recombination with embryonic stem cells. NXF(-/-) mice were morphologically indistinguishable (with no growth retardation) from their littermates (wild type) at birth. However, they started to die at a rate of 1 death/20-30 animals per week under specific pathogen-free grade breeding conditions when over 3 months old. Histological analyses revealed age-dependent neurodegeneration in brain, and only 20-30% of the NXF(-/-) mice survived for 16 months. To clarify the role of NXF in protection against neurodegeneration in normal cells, we analyzed gene expression under several conditions in vitro and in vivo. The NXF gene was up-regulated by several neurodegenerative cell-stress inducers such as thapsigargin (endoplasmic reticulum stress), SIN-1 (oxidative stress), and sorbitol (osmotic stress) in cultured cells. Furthermore, elevated NXF gene expression was apparent with in vivo stroke models featuring kainate-induced hippocampal injury and transient global ischemia. When NXF(-/-) mice were evaluated in the glutamate excitotoxicity model, they proved more susceptible to hippocampal injury at 15 weeks after birth. The findings in this study suggest that the NXF gene could be induced in response to several neurodegenerative stimuli/excitations for the cell protection, and thus provide an "on demand" cell-protection system in nervous tissue.

We studied the expression of Down's syndrome cell adhesion molecule (DSCAM) in Down's syndrome (DS) and control brains, using antisera against peptide fragments of DSCAM. On Western blots of human, mouse and rat brain homogenates, the antisera recognized a product at approximately 200 kDa. In the brain of a 2-year-old patient with DS, Western blotting revealed an overexpression of DSCAM compared to an age-matched control. Immunohistochemistry demonstrated DSCAM in the cerebral and cerebellar white matter of both control and DS subjects, in accordance with the temporal and spatial sequence of myelination. In DS brains, immunoreactivity for DSCAM, compared to that for controls, was enhanced in the Purkinje cells at all ages, and in the cortical neurons during adulthood. In demented DS patients, DSCAM immunoreactivity was observed in the core and periphery of senile plaques. The pattern of DSCAM expression suggests that it may play a role as an adhesion molecule regulating myelination. The overexpression of DSCAM may also play a role in the mental retardation and the precocious dementia of DS patients, although the mechanism of neuronal dysfunction is undetermined.

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To investigate the pathophysiologic role of myotonic dystrophy protein kinase (DMPK) in the brain in myotonic dystrophy (MD), the developmental characteristics of DMPK immunoreactivity in the central nervous system and its alteration with disease were studied. Eleven patients' brain with MD (5 congenital form, 6 adult form) were examined by immunohistochemistry using a specific antibody against synthetic DMPK peptides, antipeptide DM1, and compared with 30 control brains, including 16 age-matched controls. In controls, DM1-immunoreactive neurons appeared in the early fetal frontal cortex and cerebellar granule cell layer, persisting through 29 weeks of gestation and then disappearing. In contrast, immunoreactive neurons continued to persist in the cerebral cortex and cerebellar granule cell layer of MD patients. When we counted DM1-immunoreactive neurons, the increase over controls was greater in the congenital form of MD than in the adult form, and was greater in the cerebrum than in the cerebellum in both forms of MD. DM1 immunostaining was predominantly nuclear, mirroring Western blotting of subcellular fractions. Differences in DM1 expression related to development and to the two forms of MD may be closely related to the pathogenesis of mental retardation in this disease.