No abstract

Selenoprotein P (SePP), the major selenoprotein in plasma, has been implicated in selenium transport, selenium detoxification or antioxidant defence. We generated SePP-knockout mice that were viable, but exhibited reduced growth and developed ataxia. Selenium content was elevated in liver, but low in plasma and other tissues, and selenoenzyme activities changed accordingly. Our data reveal that SePP plays a pivotal role in delivering hepatic selenium to target tissues.

CNTF is a cytosolic molecule expressed postnatally in myelinating Schwann cells and in a subpopulation of astrocytes. Although CNTF administration prevents lesion-mediated and genetically determined motor neuron degeneration, its physiological function remained elusive. Here it is reported that abolition of CNTF gene expression by homologous recombination results in a progressive atrophy and loss of motor neurons in adult mice, which is functionally reflected by a small but significant reduction in muscle strength.CILIARY neurotrophic factor (CNTF) has many activities in vitro U , acting as a very potent survival factor for cultured parasympathetic' , sympathetic', sensory' and spinal motor neurons~· 4, and hippocampal neurons 5 . Moreover, CNTF is a cholinergic differentiation factor (increasing choline acetyltransferase ( ChAT) and reducing tyrosine hydroxylase (TH) levels) for primary cultures of rat sympathetic neurons 6 . It also promotes the survival of 0ligodendrocytes 7 and the differentiation ofO-2A glial precursor cells into type-II astrocytes in vitro8.Furthermore, the local administration of CNTF in vivo prevents the degeneration of facial nerve motor neurons after axotomy in the early postnatal period 9 and also markedly interferes with the degenerative changes in progressive motor neuronopathy (pmn) mutant mice'o . Although these observations provide promising perspectives for the therapeutic use of CNTF, the physiological function of CNTF remains elusive. CNTF is expressed postnatally in myelinating Schwann cells and in a subpopulation of astrocytes" . The structure of the molecule (lack of leader sequence) '2.13, its immunohistochemical localization in the cytosol" ·'4 and the absence of release of substantial quantities of CNTF into the culture medium of primary cultures of astrocytes'5 and transfected Cos or HeLa cells'2.13 characterize CNTF as a typical non-secreted cytosolic molecule. These characteristics strongly suggest that CNTF is not a physiological survival factor for motor neurons during embryonic development, because the period of naturally occurring motor neuron cell death in mice and rats is over at birth'6. But the cytosolic localization of CNTF and the evidence against its secretion along the classic endoplasmic reticulum (ER)-Golgi pathway does not exclude the possibility of an unconventional, regulated release, for example, as suggested for basic fibroblast growth factor (FGF)'7.'8 . The localization of CNTF in myelinating Schwann cells and its relatively high quantities in the cytosol"·'4.' 9 in comparison to its very high potency as a neurotrophic factorl.3 suggests that only a very small proportion of the cytosolic CNTF needs to reach the axons of the responsive neurons and that CNTF might have a maintenance function in postnatal neurons, in particular motor neurons. The site of synthesis and expected site of action of CNTF, together with its postnatal expression, invited an evaluation of its function by elimination of its expression by gene targeting.. Here we report on the...

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). So far, immunological mechanisms responsible for demyelination have been the focus of interest. However, mechanisms regulating axon maintenance as well as glial precursor-cell proliferation and oligodendrocyte survival might also influence disease outcome. The cytokine ciliary neurotrophic factor (CNTF), which was originally identified as a survival factor for isolated neurons, promotes differentiation, maturation and survival of oligodendrocytes. To investigate the role of endogenous CNTF in inflammatory demyelinating disease, we studied myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) in CNTF-deficient and wild-type C57BL/6 mice. Disease was more severe in CNTF-deficient mice and recovery was poor, with a 60% decrease in the number of proliferating oligodendrocyte precursor cells (OPCs) and a more than 50% increase in the rate of oligodendrocyte apoptosis. In addition, vacuolar dystrophy of myelin and axonal damage were more severe in CNTF-deficient mice. These specific pathological features could be prevented by treatment with an antiserum against tumor necrosis factor-alpha, suggesting that endogenous CNTF may counterbalance this effect of TNF-alpha (ref. 7). Here we identify a factor that modulates, in an inflammatory environment, glial cell survival and is an outcome determinant of EAE.

Bcl-2 is a major regulator of programmed cell death, a critical process in shaping the developing nervous system. To assess whether Bcl-2 is involved in regulating neuronal survival and in mediating the neuroprotective action of neurotrophic factors, we generated Bcl-2-deficient mice. At birth, the number of facial motoneurons, sensory, and sympathetic neurons was not significantly changed, and axotomy-induced degeneration of facial motoneurons could still be prevented by brain-derived neurotrophic factor (BDNF) or ciliary neurotrophic factor (CNTF). Interestingly, substantial degeneration of motoneurons, sensory, and sympathetic neurons occurred after the physiological cell death period. Accordingly, Bcl-2 is not a permissive factor for the action of neurotrophic factors, and although it does not influence prenatal neuronal survival, it is crucial for the maintenance of specific populations of neurons during the early postnatal period.