Cellular and Molecular Characteristics of CNP Suggest Regulatory Mechanisms in Myelinogenesis

Angelis, Dino De; Cox, Martha E.; Gao, Enoch; Braun, Peter E.

doi:10.1007/978-1-4615-2435-9_6

Cited by 7 publications

(5 citation statements)

References 18 publications

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“…A role for CNP in myelin formation has been predicted (De Angelis etal.,1994). Yet our earlier study showed that, despite inner tongue defects, CNP deficient compact myelin appeared normal in adult mice (Lappe‐Siefke et al,2003).…”

Section: Resultsmentioning

confidence: 99%

“…in inner and outer tongue processes and in the paranodal loops (Trapp et al,1988). In vitro , CNP copolymerizes with tubulin heterodimers thereby promoting microtubule assembly (Lee et al,2005) and also physically links tubulin and actin to membranes (Bifulco et al,2002; De Angelis and Braun,1996), through isoprenylation of its C‐terminal domain (De Angelis and Braun,1994; Esposito et al,2008). Ectopic overexpression of CNP influences process extension of oligodendrocytes in vitro and in vivo (Gravel et al,1996; Yin et al,1997).…”

Section: Introductionmentioning

confidence: 99%

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Early ultrastructural defects of axons and axon–glia junctions in mice lacking expression of Cnp1

Edgar

McLaughlin

Werner

et al. 2009

Glia

149

153

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Most axons in the central nervous system (CNS) are surrounded by a multilayered myelin sheath that promotes fast, saltatory conduction of electrical impulses. By insulating the axon, myelin also shields the axoplasm from the extracellular milieu. In the CNS, oligodendrocytes provide support for the long-term maintenance of myelinated axons, independent of the myelin sheath. Here, we use electron microscopy and morphometric analyses to examine the evolution of axonal and oligodendroglial changes in mice deficient in 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP) and in mice deficient in both CNP and proteolipid protein (PLP/DM20). We show that CNP is necessary for the formation of a normal inner tongue process of oligodendrocytes that myelinate small diameter axons. We also show that axonal degeneration in Cnp1 null mice is present very early in postnatal life. Importantly, compact myelin formed by transplanted Cnp1 null oligodendrocytes induces the same degenerative changes in shiverer axons that normally are dysmyelinated but structurally intact. Mice deficient in both CNP and PLP develop a more severe axonal phenotype than either single mutant, indicating that the two oligodendroglial proteins serve distinct functions in supporting the myelinated axon. These observations support a model in which the trophic functions of oligodendrocytes serve to offset the physical shielding of axons by myelin membranes.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Early ultrastructural defects of axons and axon–glia junctions in mice lacking expression of Cnp1

Edgar

McLaughlin

Werner

et al. 2009

Glia

149

153

View full text Add to dashboard Cite

show abstract

“…In nuclear lamin B, the carboxyl methyl group is labile only during mitosis (Chelsky et al, 1987), indicating that this modification may play some sort of regulatory role. We have demonstrated that the isoprenylated and carboxylmethylated form of CNP, but not the non-processed Cys397Ser mutant, plays a role in the formation of filopodia in transfected cells (DeAngelis et al, 1993). It will be interesting to determine if this effect is due to isoprenylation alone or whether it is regulated by the state of carboxylmethylation.…”

Section: Resultsmentioning

confidence: 96%

“…Recombinant CNP baculovirus vectors were generated from the rat CNP cDNA clone (Bernier et al, 1987), either in its native form or with a cysteine-toserine substitution in the CaaX motif (Cys397Ser) (DeAngelis et al, 1993). A BamHI site 17 nucleotides upstream of the ATG start codon was engineered by polymerase chain reaction (PCR) using standard techniques.…”

Section: Construction Of Recombinant Plasmids and Baculovirusesmentioning

confidence: 99%

C‐terminal CTII motif of 2′,3′‐cyclic nucleotide 3′‐phosphodiesterase undergoes carboxylmethylation

Cox

Gao

Braun

1994

J of Neuroscience Research

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Eukaryotic proteins with a carboxyl-terminal CaaX motif are modified by isoprenylation and subsequently processed by proteolysis of the three terminal amino acids and carboxylmethylation of the exposed cysteine residue. The myelination-associated 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP) has a C-terminal CTII sequence and is isoprenylated; however, no examples of subsequent processing exist when threonine, a polar residue, is located adjacent to the cysteine. Here we show that CNP is capable of being carboxylmethylated in both insect cells and glioma cells. This processing is dependent upon isoprenylation of the cysteine and can be inhibited with the isoprenylated cysteine derivative, N-acetyl-S-farnesyl-L-cysteine. Although the role of the methyl group at the C-terminus of other isoprenylated proteins is not fully understood, modulation of signal transduction pathways is strongly indicated. This modification of CNP may similarly regulate cell biological processes in myelinogenesis.

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“…4) variety of proteins essential to signal transduction cascades (Clarke, 1992) and because of post-translational modifications (i3oprenylation and carboxylmethylation) of the cysteine that confer biologically important properties on these proteins (Clarke, 1992). Results of our previous and ongoing investigation of this modified C-terminal cysteine in CNP underscore its significance in cell biology (Braun et al, 1991;DeAngelis et al, 1993). Phosphorylation of CNP2 in vitro and in vivo has been reported (Bradbury et al, 1984;Sprinkle, 1989;Thompson, 1992), although the phosphorylated sites were not identified.…”

Section: Agaggtggtaatt~gggctgggtcattggc~tggagcggccacctagatgcacccaggacmentioning

confidence: 97%

Molecular cloning and characterization of rat brain 2′, 3′ ‐cyclic nucleotide 3′ ‐phosphodiesterase isoform 2

Gravel

DeAngelis

Braun

1994

J of Neuroscience Research

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We have isolated a cDNA coding for the larger isoform of the rat brain 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP2), a protein associated with myelination in the central nervous system (CNS). The complete 420 amino acid sequence was deduced from the nucleotide sequence of the cDNA. Sequence comparisons show that rat CNP shares 96% homology with mouse, 84% with bovine, and 86% with human CNP. Errors in the published sequence of rat CNP1 have now been corrected. Comparisons with other proteins reveal several interesting conserved motifs, including two leucine repeat heptads, and two consensus motifs for phosphorylation in the N-terminal domain of CNP2.

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Cellular and Molecular Characteristics of CNP Suggest Regulatory Mechanisms in Myelinogenesis

Cited by 7 publications

References 18 publications

Early ultrastructural defects of axons and axon–glia junctions in mice lacking expression of Cnp1

Early ultrastructural defects of axons and axon–glia junctions in mice lacking expression of Cnp1

C‐terminal CTII motif of 2′,3′‐cyclic nucleotide 3′‐phosphodiesterase undergoes carboxylmethylation

Molecular cloning and characterization of rat brain 2′, 3′ ‐cyclic nucleotide 3′ ‐phosphodiesterase isoform 2

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