Disease relevance of Cnp1

• Thus O4 positive O-2A progenitor cells proliferate early in the course of the demyelinating disease, while CNP positive oligodendrocytes do not [1].
• Even cells from a C6 rat glioma cell line, which contain very little of CNP, were labeled by the monoclonal antibody [2].
• These antibodies were used to identify, in a rat brain phage lambda gt11 expression library, cDNA clones encoding beta-galactosidase-CNP fusion proteins, some of which showed CNP activity [3].
• Cyclic nucleotide phosphodiesterase 3A-deficient mice as a model of female infertility [4].
• A combination of pharmacological and genetic approaches was used to determine the role of type 4 cAMP-specific cyclic nucleotide phosphodiesterase 4 (PDE4) in reversing alpha(2)-adrenoceptor-mediated anesthesia, a behavioral correlate of emesis in non-vomiting species [5].

High impact information on Cnp1

• Here we show that Cnp1, which encodes 2',3'-cyclic nucleotide phosphodiesterase in oligodendrocytes, is essential for axonal survival but not for myelin assembly [6].
• In the absence of glial cyclic nucleotide phosphodiesterase, mice developed axonal swellings and neurodegeneration throughout the brain, leading to hydrocephalus and premature death [6].
• Increased cyclic nucleotide phosphodiesterase activity in leukaemic lymphocytes [7].
• Since cAMP blocks meiotic maturation of mammalian and amphibian oocytes in vitro and cyclic nucleotide phosphodiesterase 3A (PDE3A) is primarily responsible for oocyte cAMP hydrolysis, we generated PDE3A-deficient mice by homologous recombination [4].
• Theophylline, an inhibitor of cyclic nucleotide phosphodiesterase, elevated intracellular cAMP [8].

Chemical compound and disease context of Cnp1

• A novel variant of the S49 mouse lymphoma has been selected from wild-type cells by growth in medium containing the beta-adrenergic agonist terbutaline and inhibitors of cyclic nucleotide phosphodiesterase [9].
• A cyclic nucleotide phosphodiesterase inhibitor, 1-methyl-3-isobutylxanthine, promoted the differentiation and maturation of B16 melanoma cells, phenomena associated with biological alterations in the surface properties of the cells [10].
• Prostaglandin E1, a stimulator of adenylate cyclase, plus beta-carotene, and 4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (Ro 20-1724), an inhibitor of cyclic nucleotide phosphodiesterase, plus beta-carotene were used to induce terminal differentiation in > 90% of neuroblastoma cells [11].
• Comparative study of the effects of cyclic nucleotide phosphodiesterase inhibitors on bone resorption and cyclic AMP formation in vitro [12].
• To elucidate the disturbances of myelin metabolism in the nerve tissue of murine muscular dystrophy, the lipid composition of and the developmental changes in 2', 3'-cyclic nucleotide 3'-phosphohydrolase (CNPase) and cholesterol ester hydrolase (CEHase) activities in the purified CNS myelin of dystrophic mice were determined [13].

Biological context of Cnp1

• There are two genetic loci identified by CNP probes, one is closely linked to the GFAP gene, and the other maps to chromosome 3 [14].
• This is consistent with the experimental observations that PLP acts like an ionophore or proton channel when reconstituted into planar lipid bilayers, MBP binds GTP, and CNP catalyzes in vitro the hydrolysis of 2',3'-nucleotides into corresponding 2'-nucleotides [15].
• Further, ODC that overexpress CNP appear to mature earlier in development, resulting in earlier maximum gene expression for myelin basic proteins and proteolipid protein [16].
• Alternative splicing of mouse brain 2',3'-cyclic-nucleotide 3'-phosphodiesterase mRNA [17].
• Since EGF is a strong mitogen for 1H91 cells, and these cells may be differentiated into GFAP positive, A2B5 negative, CNPase negative astrocytes, we conclude that 1H91 cells conform to a type-1 astrocyte precursor phenotype [18].

Anatomical context of Cnp1

• We report that Cnp1-null mice, lacking expression of the myelin protein cyclic nucleotide phosphodiesterase (CNP), have disrupted axoglial interactions in the central nervous system (CNS) [19].
• Immunohistochemical localization of 2',3'-cyclic nucleotide 3'-phosphodiesterase and myelin basic protein in the central nervous system of the jimpy and the normal mouse [20].
• 5. MBP mRNA was detected even later (E14.5), and, in addition, only in the caudal (rhombencephalon and spinal cord) territories of expression of dm-20 and CNP [21].
• Two proteins with CNP activity are known to exist in brain and lymphoid tissues [14].
• In mld and control myelin, CNP-specific activities decreased during development suggesting a preferential localization of CNP in Schwann cell plasma membranes [22].

Associations of Cnp1 with chemical compounds

• As remyelination proceeded, CNP immunostaining returned to near normal and tritiated thymidine injected previously during the demyelinating phase now appeared in CNP+ oligodendrocytes [1].
• On the other hand, modification studies with diethyl pyrocarbonate indicated that two histidines are essential for CNPase activity [23].
• Identification of essential residues in 2',3'-cyclic nucleotide 3'-phosphodiesterase. Chemical modification and site-directed mutagenesis to investigate the role of cysteine and histidine residues in enzymatic activity [23].
• We report that early-passage C6 glial cells continue to be bipotential cells and when grown in the absence of serum express high GS and CNP activities correlating with the high number of GFAP- and GalC-positive cells, respectively [24].
• In addition, the myelin-associated enzyme 2',3'-cyclic nucleotide 3'-phosphodiesterase, tubulin, and actin tended to be resistant to Triton extraction [25].

Regulatory relationships of Cnp1

• Bundling of actin filaments occurs only around MBP domains, and the colocalization of CNPase along microtubular structures also appears to be regulated by MBP domains in sheets [26].
• Using a transgenic mouse, we show that NG2 proteoglycan-positive progenitor cells that express the 2',3'-cyclic nucleotide 3'-phosphodiesterase gene display a multipotent phenotype in vitro and generate electrically excitable neurons, as well as astrocytes and oligodendrocytes [27].
• Activation of G(i) family G proteins can lower cAMP by inhibiting adenylate cyclase or stimulating a cyclic nucleotide phosphodiesterase, but we show here that inhibition of this class of G proteins by injection of pertussis toxin into follicle-enclosed mouse oocytes does not prevent meiotic resumption in response to LH [28].
• Membrane-permeable cAMP analogs or elevation of intracellular cAMP by cyclic nucleotide phosphodiesterase (PDE) inhibitors activates cAMP-dependent protein kinase [29].
• We have cloned from mouse testis a novel calmodulin-stimulated cyclic nucleotide phosphodiesterase 1A isoform, Pde1a_v7 (mmPDE1A7), which arises from an alternative transcription start in the cyclic nucleotide phosphodiesterase 1A gene [30].

Other interactions of Cnp1

• In controls, the CNPase and MBP were localized exclusively in white matter in the CNS [20].
• No abnormal accumulation of MAG, MBP, or CNP in the cell body was found [31].
• These changes are characterized by mislocalized Caspr immunostaining, combined with a decrease of clustered Na+ channels, and occur before axonal degeneration and microglial invasion, both prominent in older Cnp1-null mice [19].
• Importance of cAMP-response element-binding protein in regulation of expression of the murine cyclic nucleotide phosphodiesterase 3B (Pde3b) gene in differentiating 3T3-L1 preadipocytes [32].
• Furthermore, significant reductions of CNPase and 120 kD NCAM were also present at 2 months, indicating that the oligodendroglial abnormalities begin at a relatively early age [33].

Analytical, diagnostic and therapeutic context of Cnp1

• Double immunofluorescence microscopy revealed that all GFAP-IR cells (type 1 and type 2 astrocytes), all CNP- or MBP-IR cells (oligodendrocytes), as well as immature and intermediate cell types expressed GR, although at different levels [34].
• Oligodendrocytes or their putative progenitors were the only cells found to be immunoreactive to polyclonal antisera against the enzyme 2'3'-cyclic nucleotide 3'-phosphodiesterase (CNP) in developing and mature brains of rats and mice, as visualized by light and electron microscopy [35].
• Immunoprecipitation experiments using a polyclonal antibody directed against CNP detect both CNP isoforms in tissues or cell lines expressing only the CNP2 transcript [36].
• A cDNA fragment of mouse 2',3'-cyclic-nucleotide 3'-phosphodiesterase was isolated and used as the probe for Northern blot analysis [37].
• The two closely spaced protein bands observed on SDS-PAGE and previously stained on immunoblots of CNS CNPase using polyvalent rabbit anti-bovine CNPase antisera, and now different monoclonal antibodies, appear to be immunologically related and to contain highly conserved sequences [38].

References