Promyelinating drugs ameliorate oligodendrocyte pathologies in a mouse model of Krabbe disease.

Krabbe disease (KD) is a rare inherited demyelinating disorder caused by a deficiency in the lysosomal enzyme galactosylceramide (GalCer) β-galactosidase. Most patients with KD exhibit fatal cerebral demyelination with apoptotic oligodendrocyte (OL) death and die before the age of 2-4 years. We have previously reported that primary OLs isolated from the brains of twitcher (twi) mice, an authentic mouse model of KD, have cell-autonomous developmental defects and undergo apoptotic death accompanied by abnormal accumulation of psychosine, an endogenous cytotoxic lyso-derivative of GalCer.

A Support System for Adolescent and Young Adult Patients with Cancer at a Comprehensive Cancer Center.

Cancer patients in adolescents and young adults (AYA) generation aged 15-39 years have various psychosocial needs during their treatment course such as school enrollment, finding employment, marriage, and fertility. It is difficult for medical professionals to gain experience related to providing medical care and consultation support to these kinds of AYA generation cancer patients. There is a need to provide information and establish both support and medical care systems that are able to meet the diverse needs unique to this generation.

Reduction in miR-219 expression underlies cellular pathogenesis of oligodendrocytes in a mouse model of Krabbe disease.

Krabbe disease (KD), also known as globoid cell leukodystrophy, is an inherited demyelinating disease caused by the deficiency of lysosomal galactosylceramidase (GALC) activity. Most of the patients are characterized by early-onset cerebral demyelination with apoptotic oligodendrocyte (OL) death and die before 2 years of age. However, the mechanisms of molecular pathogenesis in the developing OLs before death and the exact causes of white matter degeneration remain largely unknown.

Developmental defects and aberrant accumulation of endogenous psychosine in oligodendrocytes in a murine model of Krabbe disease.

Krabbe disease (KD), or globoid cell leukodystrophy, is an inherited lysosomal storage disease with leukodystrophy caused by a mutation in the galactosylceramidase (GALC) gene. The majority of patients show the early onset form of KD dominated by cerebral demyelination with apoptotic oligodendrocyte (OL) death. However, the initial pathophysiological changes in developing OLs remain poorly understood.

Glutamate-dependent ectodomain shedding of neuregulin-1 type II precursors in rat forebrain neurons.

The neurotrophic factor neuregulin 1 (NRG1) regulates neuronal development, glial differentiation, and excitatory synapse maturation. NRG1 is synthesized as a membrane-anchored precursor and is then liberated by proteolytic processing or exocytosis. Mature NRG1 then binds to its receptors expressed by neighboring neurons or glial cells.

Intrinsic and extrinsic mechanisms control the termination of cortical interneuron migration.

During development, neurons migrate from their site of origin to their final destinations. Upon reaching this destination, the termination of their migration is crucial for building functional architectures such as laminated structures and nuclei. How this termination is regulated, however, is not clear.

Gene induction in mature oligodendrocytes with a PLP-tTA mouse line.

Mature oligodendrocytes are critical for myelin maintenance. To understand the molecular basis for this, genetic manipulation of mature oligodendrocytes is needed. Here we generated a mature oligodendrocyte tTA (tetracycline-controlled transcriptional activator) mouse line which, in combination with a tTA-dependent promoter line driving the expression of the desired transgene, can be used for gain-of-function studies.

Olig2 lineage cells generate GABAergic neurons in the prethalamic nuclei, including the zona incerta, ventral lateral geniculate nucleus and reticular thalamic nucleus.

Neuronal differentiation is a crucial event during neural development. Recent studies have characterized the development of the diencephalon; however, the origins of the primarily GABAergic prethalamic nuclei, including the zona incerta (ZI), ventral lateral geniculate nucleus (vLG) and reticular thalamic nucleus (RT), remain unclear. Here we characterize Olig2 lineage cells in the developing prethalamus using mice in which tamoxifen-induced recombination permanently labels Olig2-expressing cells.

Flexible Accelerated STOP Tetracycline Operator-knockin (FAST): a versatile and efficient new gene modulating system.

We created the Flexible Accelerated STOP Tetracycline Operator (tetO)-knockin (FAST) system, an efficient method for manipulating gene expression in vivo to rapidly screen animal models of disease. A single gene targeting event yields two distinct knockin mice-STOP-tetO and tetO knockin-that permit generation of multiple strains with variable expression patterns: 1) knockout, 2) Cre-mediated rescue, 3) tetracycline-controlled transcriptional activator (tTA)-mediated misexpression, 4) tetracycline-controlled transcriptional activator (tTA)-mediated overexpression, and 5) tetracycline-controlled transcriptional silencer (tTS)-mediated conditional knockout/knockdown. Using the FAST system, multiple gain-of-function and loss-of-function strains can therefore be generated on a time scale not previously achievable.

Brain-derived neurotrophic factor enhances the basal rate of protein synthesis by increasing active eukaryotic elongation factor 2 levels and promoting translation elongation in cortical neurons.

The constitutive and activity-dependent components of protein synthesis are both critical for neural function. Although the mechanisms controlling extracellularly induced protein synthesis are becoming clear, less is understood about the molecular networks that regulate the basal translation rate. Here we describe the effects of chronic treatment with various neurotrophic factors and cytokines on the basal rate of protein synthesis in primary cortical neurons.

Enhancement of translation elongation in neurons by brain-derived neurotrophic factor: implications for mammalian target of rapamycin signaling.

The effects and signaling mechanisms of brain-derived neurotrophic factor (BDNF) on translation elongation were investigated in cortical neurons. BDNF increased the elongation rate approximately twofold, as determined by measuring the ribosomal transit time. BDNF-accelerated elongation was inhibited by rapamycin, implicating the mammalian target of rapamycin (mTOR).

Brain-derived neurotrophic factor induces mammalian target of rapamycin-dependent local activation of translation machinery and protein synthesis in neuronal dendrites.

In neurons, perisynaptic or dendritic translation is implicated in synapse-wide alterations of function and morphology triggered by neural activity. The molecular mechanisms controlling local translation activation, however, have yet to be elucidated. Here, we show that local protein synthesis and translational activation in neuronal dendrites are upregulated by brain-derived neurotrophic factor (BDNF) in a rapamycin and small interfering RNA specific for mammalian target of rapamycin (mTOR)-sensitive manner.

Developmental changes of eukaryotic initiation factor 2B subunits in rat hippocampus.

Regulated protein synthesis is critical for neural development, such as the formation of synapses and neural circuits and the modulation of synaptic plasticity. Protein synthesis is controlled by translation factors, including initiation, elongation and release factors. Here we investigated the developmental changes of eukaryotic initiation factor 2B (eIF2B) subunits in rat hippocampus.

Cellular and subcellular distributions of translation initiation, elongation and release factors in rat hippocampus.

Novel protein synthesis in the brain has been suggested to contribute to the formation of synapses and neural circuits during development and the modulation of long-term synaptic plasticity through life. However, cellular and subcellular distribution of neuronal translation machinery and regulator molecules has not yet been extensively characterized in rat brain. In this report, the distribution of translation factors in the developing hippocampus, a region which is highly plastic, was analyzed by immunohistochemistry and Western blotting.