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...
The neuropeptide receptors which are present in very small quantities in the cell and are embedded tightly in the plasma membrane have not been well characterized. Mammals contain three distinct tachykinin neuropeptides, substance P, substance K and neuromedin K, and it has been suggested that there are multiple tachykinin receptors. By electrophysiological measurement, we have previously shown that Xenopus oocytes injected with brain and stomach mRNAs faithfully express mammalian substance-P and substance-K receptors, respectively. Here we report the isolation of the cDNA clone for bovine substance-K receptor (SKR) by extending this method to develop a new cloning strategy. We constructed a stomach cDNA library with a cloning vector that allowed in vitro synthesis of mRNAs and then identified a particular cDNA clone by testing for receptor expression following injection of the mRNAs synthesized in vitro into the oocyte system. Because oocytes injected with exogenous mRNAs can express numerous receptors and channels, our new strategy will be applicable in the general molecular cloning of these proteins. The result provides the first indication that the neuropeptide receptor has sequence similarity with rhodopsin-type receptors (the G-protein-coupled receptor family) and thus possesses multiple membrane-spanning domains.
Neurotrophin-3 (NT-3) is required for the development of most sensory neurons of the dorsal root ganglia. Using electrophysiological techniques in mice with null mutations of the NT-3 gene, we show that two functionally specific subsets of cutaneous afferents differentially require this factor: D-hair receptors and slowly adapting mechanoreceptors; other cutaneous receptors were unaffected. Merkel cells, which are the end organs of slowly adapting mechanoreceptors, are virtually absent in 14-day-old homozygous mutants and are severely reduced in adult NT-3 heterozygous animals. This loss of Merkel cells, together with their innervation, happens in the first postnatal weeks of life, in contrast to muscle spindles and afferents, which are never formed in the absence of NT-3. Thus, NT-3 is essential for the maintenance of specific cutaneous afferents known to subserve fine tactile discrimination in humans.
Degenerative disorders of the nervous system, in particular those of motoneurons, may be based on multifactorial inherited and/or acquired defects which individually do not result in degenerative disorders, but which become apparent when additional (cryptic) inherited disturbances or sub-threshold concentrations of noxious factors come into play. Accordingly, the inherited inactivation of the CNTF gene in a high proportion of the Japanese population may represent a predisposing factor for degenerative disorders of motoneurons.
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