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Interleukin (IL)-18 induces T cells and natural killer cells to produce not only interferon-γ but also other cytokines by binding to the IL-18 receptor (IL-18R) α and β subunits. However, little is known about how IL18, IL-18Rα, and IL-18Rβ form a high-affinity complex on the cell surface and transduce the signal. We found that IL-18 and IL-18Rα bind to glycosylphosphatidylinositol (GPI) glycan via the third mannose 6-phosphate diester and the second β-GlcNAc-deleted mannose 6-phosphate of GPI glycan, respectively. To determine which GPIanchored glycoprotein is involved in the complex of IL-18 and IL-18Rα, IL-18Rα of IL-18-stimulated KG-1 cells was immunoprecipitated together with CD48 by anti-IL-18Rα antibody. More than 90% of CD48 was detected as β-GlcNAc-deleted GPI-anchored glycoprotein, and soluble recombinant human CD48 without GPI glycan bound to IL-18Rα, indicating that CD48 is associated with IL-18Rα via both the peptide portion and the GPI glycan. To investigate whether the carbohydrate recognition of IL-18 is involved in physiological activities, KG-1 cells were digested with phosphatidylinositol-specific phospholipase C before IL-18 stimulation. Phosphatidylinositol-specific phospholipase C treatment inhibited the phosphorylation of tyrosine kinases and the following IL-18-dependent interferon-γ production. These observations suggest that the complex formation of IL-18·IL-18Rα·CD48 via both the peptide portion and GPI glycan triggers the binding to IL-18Rβ, and the IL-18-IL-18Rα-CD48·IL-18Rβ complex induces cellular signaling. [ABSTRACT FROM AUTHOR]

Presents study findings showing that a beta-N-acetylglucosaminyl phosphate diester residue is attached to the glycosylphosphatidylinositol (GPI) anchor of human placental alkaline phosphatase (AP). Evidence that both sialidase-treated soluble AP and its GPI-anchored glycan bound to a Psatyrella velutina lectin-Sepharose column; Analysis of trypsin-digested sAP; Finding that the beta-N-acetylglucosaminyl phosphate diester residue is important for GPI anchor recognition of aerolysin.

Effects of weak amines on the proteolytic conversions of proalbumin to serum were studied in primary culture of rat hepatocytes. In control culture proalbumin was converted to serum albunin was inhibited and proalbunin per se was released into, medium. A similar inhibition of the processing was also observed in the presence of other amines such as methylamine and NH4Cl. Thus weak amines mimic the carboxylic ionophore monensin with regard to the effet on proalbunin conversion [Oda & Ikehara (1982) Biochem, Biophys. Res. Commun, 105, 766-772]. Since proteolytic conversion of proalbunin is believed to occur at the Golgi complex, these results suggest that weakly basic amines perturb the Golgi complex in addition to lysosomes and endosomes. [ABSTRACT FROM AUTHOR]

Focuses on α&supl;-protease inhibitors. Determination of the genetic type of the protease inhibitor by autosomal co-dominant alleles; Presence of multiple genetic variants of the protease inhibitor. [ABSTRACT FROM AUTHOR]

Nordihydroguaiaretic acid (NDGA), an inhibitor of lipoxygenase, blocks protein transport from the endoplasmic reticulum (ER) to the Golgi complex and induces the redistribution of Golgi proteins into the ER. We investigated characteristics of NDGA-induced retrograde movement of the Golgi proteins to the ER. At an early stage of incubation of cells with NDGA, the Golgi complex formed convoluted membrane aggregates. Electron microscopy revealed that these aggregates directly interact en bloc with the ER membrane. The direct interaction and subsequent incorporation of the Golgi proteins into the ER were found to be temperature-dependent. The protein of ER–Golgi intermediate compartment (ERGIC), ERGIC53, was rapidly accumulated in the Golgi upon treatment with NDGA. This accumulation was significantly inhibited by low temperature at 15 °C. Under the condition, the redistribution of the Golgi proteins into the ER as well as the direct interaction between the ER and the Golgi by NDGA were also inhibited, suggesting an important role of the ERGIC in the retrograde movement. In contrast, the low temperature did not inhibit formation of the Golgi aggregates by NDGA. Taken together, these results suggest that NDGA causes the redistribution of the Golgi proteins into the ER through the direct connections between the Golgi, the ERGIC, and the ER. [Copyright &y& Elsevier]

The N-linked sugar chains of alkaline phosphatases, purified from rat AH-130 hepatoma and from normal rat liver, were released quantitatively as oligosaccharides by hydrazinolysis and were labeled by reduction with NaB 3H4 A comparative study of their structures revealed that the following structural differences are induced by hepatocyte carcinogenesis: complex-type tetraantennary sugar chains and hybrid-type sugar chains appear; outer-chain moieties of the sugar chains of the hepatoma enzyme contain exclusively the Gal(β1-4)GIcNAc groups (type 2 chains) but those of the normal enzyme contain other Gal(Beta;1)GIcNAc groups and type 2 chains: and novel fucosylated high-mannose-type sugar chains are found in the oligosaccharides of the hepatoma enzyme. [ABSTRACT FROM AUTHOR]

We have studied the biosynthesis and intracellular processing of three major secretory proteins, albumin, α1-protease inhibitor and α2u-globulin, in cultured rat hepatocytes. The effect of secretion-blocking agents, monensin, a monovalent ionophore, and the microtubule-affecting agents colchicine and taxol was determined. In the control cells, α1-protease inhibitor, a glycoprotein, was first synthesized as an endoglycosidase-H-sensitive form with Mr 51000, and then processed to two endoglycosidase-H-resistant forms having Mr 51000 and 56000, the latter of which was secreted into the medium. Initially synthesized proalbumin was converted with chase to serum-type albumin, while no pro-type precursor was identified for α2u-globulin. In the cells lrcated with colchicine or taxol, in which secretion was greatly inhibited, the fully processed α1-protease inhibitor and albumin accumulated and were finally secreted into the medium. In the monensin-treated cells, however, most of the newly synthesized α1-protease inhibitor and albumin were not processed to the final mature forms, resulting in accumulation of two 51000-Mr forms and proalbumin, respectively. Moreover in treated cells, proalbumin and the endoglycosidase-H-resistant α1-protease inhibitor were finally secreted into the medium. Such an effect was not caused by NH4Cl which also inhibited the secretion and is known to exert the similar effect as monensin on the receptor-mediated endocytosis pathway. Based on these results, the use of monensin may prove valuable for more detailed analysis of intracellular processing of various proteins. [ABSTRACT FROM AUTHOR]

p230/golgin-245 is a trans -Golgi coiled-coil protein that is known to participate in regulatory transport from the trans -Golgi network (TGN) to the cell surface. We investigated the role of p230 and its interacting protein, microtubule actin crosslinking protein 1 (MACF1), in amino acid starvation-induced membrane transport. p230 or MACF1 knock-down (KD) cells failed to increase the autophagic flow rate and the number of microtubule-associated protein 1 light chain 3 (LC3)-positive puncta under starvation conditions. Loss of p230 or MACF1 impaired mAtg9 recruitment to peripheral phagophores from the TGN, which was observed in the early step of autophagosome formation. Overexpression of the p230-binding domain of MACF1 resulted in the inhibition of mAtg9 trafficking in starvation conditions as in p230-KD or MACF1-KD cells. These results indicate that p230 and MACF1 cooperatively play an important role in the formation of phagophore through starvation-induced transport of mAtg9-containing membranes from the TGN. In addition, p230 itself was detected in autophagosomes/autolysosome with p62 or LC3 during autophagosome biogenesis. Thus, p230 is an important molecule in phagophore formation, although it remains unclear whether p230 has any role in late steps of autophagy. [ABSTRACT FROM AUTHOR]

The coiled-coil Golgi membrane protein golgin-84 functions as a tethering factor for coat protein I (COPI) vesicles. Protein interaction analyses have revealed that golgin-84 interacts with another tether, the conserved oligomeric Golgi (COG) complex, through its subunit Cog7. Therefore, we explored the function of golgin-84 as the tether for COPI vesicles of intra-Golgi retrograde traffic. First, glycosylic maturation of both plasma membrane (CD44) and lysosomal (lamp1) glycoproteins was distorted in golgin-84 knockdown (KD) cells. The depletion of golgin-84 caused fragmentation of the Golgi with the mislocalization of Golgi resident proteins, resulting in the accumulation of vesicles carrying intra-Golgi solubleN-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) and cis-Golgi membrane protein GPP130. Similar observations were obtained by diminution of the COG complex, suggesting a strong correlation between the two tethers. Indeed, COG complex-dependent (CCD) vesicles that accumulate in Cog3 or Cog7 KD cells carried golgin-84. Surprisingly, the interaction between golgin-84 and another candidate tethering partner CASP (CDP/cut alternatively spliced product) decreased in Cog3 KD cells. These results indicate that golgin-84 on COPI vesicles interact with the COG complex before SNARE assembly, suggesting that the interaction of golgin-84 with COG plays an important role in the tethering process of intra-Golgi retrograde vesicle traffic. [ABSTRACT FROM AUTHOR]

The vesicle-tethering protein p115 functions in endoplasmic reticulum–Golgi trafficking. We explored the function of homologous region 2 (HR2) of the p115 head domain that is highly homologous with the yeast counterpart, Uso1p. By expression of p115 mutants in p115 knockdown (KD) cells, we found that deletion of HR2 caused an irregular assembly of the Golgi, which consisted of a cluster of mini-stacked Golgi fragments, and gathered around microtubule-organizing center in a microtubule-dependent manner. Protein interaction analyses revealed that p115 HR2 interacted with Cog2, a subunit of the conserved oligomeric Golgi (COG) complex that is known another putative cis-Golgi vesicle-tethering factor. The interaction between p115 and Cog2 was found to be essential for Golgi ribbon reformation after the disruption of the ribbon by p115 KD or brefeldin A treatment and recovery by re-expression of p115 or drug wash out, respectively. The interaction occurred only in interphase cells and not in mitotic cells. These results strongly suggested that p115 plays an important role in the biogenesis and maintenance of the Golgi by interacting with the COG complex on the cis-Golgi in vesicular trafficking. [ABSTRACT FROM AUTHOR]

Mammalian serine racemase is a brain-enriched enzyme that converts L- into D-serine in the nervous system. D-Serine is an endogenous co-agonist at the ‘glycine site’ of N-methyl D-aspartate (NMDA) receptors that is required for the receptor/channel opening. Factors regulating the synthesis of D-serine have implications for the NMDA receptor transmission, but little is known on the signals and events affecting serine racemase levels. We found that serine racemase interacts with the Golgin subfamily A member 3 (Golga3) protein in yeast two-hybrid screening. The interaction was confirmed in vitro with the recombinant proteins in co-transfected HEK293 cells and in vivo by co-immunoprecipitation studies from brain homogenates. Golga3 and serine racemase co-localized at the cytosol, perinuclear Golgi region, and neuronal and glial cell processes in primary cultures. Golga3 significantly increased serine racemase steady-state levels in co-transfected HEK293 cells and primary astrocyte cultures. This observation led us to investigate mechanisms regulating serine racemase levels. We found that serine racemase is degraded through the ubiquitin-proteasomal system in a Golga3-modulated manner. Golga3 decreased the ubiquitylation of serine racemase both in vitro and in vivo and significantly increased the protein half-life in pulse-chase experiments. Our results suggest that the ubiquitin system is a main regulator of serine racemase and n-serine levels. Modulation of serine racemase degradation, such as that promoted by Golga3, provides a new mechanism for regulating brain D-serine levels and NMDA receptor activity. [ABSTRACT FROM AUTHOR]

Abstract: Serum alkaline phosphatase (ALP) is a representative marker of cholestasis, in diseases such as primary biliary cirrhosis (PBC). However, the hepatic localization of ALP in patients with cholestatic liver diseases has not been fully clarified. Accordingly, we studied the expression of ALP in the liver of PBC, chronic hepatitis C and controls. By immunohistochemistry, in the liver tissue of controls and chronic hepatitis C patients, ALP was found to be localized in the canalicular membrane of hepatocytes and the apical area of the cytoplasm of bile duct epithelial cells. In PBC, ALP was localized in both the canalicular and baso-lateral membranes of hepatocytes and in the whole cytoplasm of the remaining bile duct epithelial cells. The expression of ALP in liver tissues evaluated by Western blotting was increased to 3.6-fold in PBC compared with that in the controls and chronic hepatitis C patients, while the expression of mRNA of ALP evaluated by RT-PCR was increased to 7.0-fold in PBC compared with that in the controls and chronic hepatitis C patients. The present study is the first study to reveal altered localization and increased expression of ALP which may result in the elevation of serum ALP in PBC. [Copyright &y& Elsevier]

Abstract: Depletion of p115 with small interfering RNA caused fragmentation of the Golgi apparatus, resulting in dispersed distribution of stacked short cisternae and a vesicular structure (mini-stacked Golgi). The mini-stacked Golgi with cis- and trans-organization is functional in protein transport and glycosylation, although secretion is considerably retarded in p115 knockdown cells. The fragmented Golgi was further disrupted by treatment with breferdin A and reassembled into the mini-stacked Golgi by removal of the drug, as observed in control cells. In addition, p115 knockdown cells maintained retrograde transport from the Golgi to the endoplasmic reticulum, although the rate was not as efficient as in control cells. While no alternation of microtubule networks was found in p115 knockdown cells, the fragmented Golgi resembled those in cells treated with anti-microtubule drugs. The results suggest that p115 is involved in vesicular transport between endoplasmic reticulum and the Golgi, along with microtubule networks. [Copyright &y& Elsevier]

GCP170, a member of the golgin family associated with the cytoplasmic face of the Golgi membrane, was found to have a Golgi localization signal at the NH[sub 2]terminal region (positions 137-237). Using this domain as bait in the yeast two-hybrid screening system, we identified a novel protein that interacted with GCP170. The 2.0-kilobase mRNA encoding a 137-amino acid protein of 16 kDa designated GCP16 was ubiquitously expressed. Immunofluorescence microscopy showed that GCP16 was co-localized with GCP170 and giantin in the Golgi region. Despite the absence of a hydrophobic domain sufficient for participating in membrane localization, GCP16 was found to be tightly associated with membranes like an integral membrane protein. Labeling experiments with [³H]palmitic acid and mutational analysis demonstrated that GCP16 was acylated at Cys[sup 69] and Cys[sup 72], accounting for its tight association with the membrane. A mutant without potential acylation sites (C69A/C72A) was no longer localized to the Golgi, indicating that the acylation is prerequisite for the Golgi localization of GCP16. Although the mutant GCP16, even when overexpressed, had no effect on protein transport, overexpression of the wild type GCP16 caused an inhibitory effect on protein transport from the Golgi to the cell surface. Taken together, these results indicate that GCP16 is the acylated membrane protein, associated with GCP170, and possibly involved in vesicular transport from the Golgi to the cell surface. [ABSTRACT FROM AUTHOR]

Subthreshold-activating somatodendritic A-type potassium channels have fundamental roles in neuronal signaling and plasticity which depend on their unique cellular localization, voltage dependence, and kinetic properties. Some of the components of A-type K+ channels have been identified; however, these do not reproduce the properties of the native channels, indicating that key molecular factors have yet to be unveiled. We purified A-type K+ channel complexes from rat brain membranes and found that DPPX, a protein of unknown function that is structurally related to the dipeptidyl aminopeptidase and cell adhesion protein CD26, is a novel component of A-type K+ channels. DPPX associates with the channels'' pore-forming subunits, facilitates their trafficking and membrane targeting, reconstitutes the properties of the native channels in heterologous expression systems, and is coexpressed with the pore-forming subunits in the somatodendritic compartment of CNS neurons. [Copyright &y& Elsevier]

Integrating the pleomorphic membranes of the intermediate compartment (IC) into the array of Golgi cisternae is a crucial step in membrane transport, but it is poorly understood. To gain insight into this step, we investigated the dynamics by which cis-Golgi matrix proteins such as GM130 and GRASP65 associate with, and incorporate, incoming IC elements. We found that GM130 and GRASP65 cycle via membranous tubules between the Golgi complex and a constellation of mobile structures that we call late IC stations. These stations are intermediate between the IC and the cis-Golgi in terms of composition, and they receive cargo from earlier IC elements and deliver it to the Golgi complex. Late IC elements are transient in nature and sensitive to fixatives; they are seen in only a fraction of fixed cells, whereas they are always visible in living cells. Finally, late IC stations undergo homotypic fusion and establish tubular connections between themselves and the Golgi. Overall, these features indicate that late IC stations mediate the transition between IC elements and the cis-Golgi face. [ABSTRACT FROM AUTHOR]

Presents a study on the glycophosphatidylinositol (GPI) anchors of placental alkaline phosphatase (PLAP) proteins expressed by two K562 lines differing in acylation of the GPI anchors in their endogenous surface proteins. Methodology used in the study; Determinants of GPI anchor modification; Results of analyses of purified 14C-labeled endogenous PLAP protein; Discussion on the findings of the study.

A cDNA encoding a 5′-nucleotidase was identified by screening a λgt10 cDNA library from the electric lobe of Discopyge ommata using a cDNA probe containing the complete open reading frame coding for the rat liver enzyme. Nucleotide sequence analysis defines an open reading frame of 577 amino acids, corresponding to a calculated molecular mass of 63833 Da. The N-terminus of the mature protein, as determined by direct protein sequencing, is preceded by 29 amino acid residues comprising a signal peptide. The C-terminus contains a stretch of hydrophobic amino adds, considered to be cleaved on post-translational modification and exchanged for glycosylphosphatidylinositol as a membrane anchor. The predicted protein contains four potential N-linked glycosylation sites. Electric ray 5′-nucleotidase shares 61 % amino acid identity with the enzymes from rat liver and human placenta, and about 23% with bacterial proteins possessing 5′-nucleotidase activity and also additional enzyme activities like UDP-glucose hydrolase. Polyclonal antibodies raised against 5′-nucleotidase from mammalian sources or the electric ray electric organ reveal mutual cross-reactivity. Interestingly, there are 5–7 domains highly conserved in procaryotes and vertebrates in enzymes exhibiting 5′-nucleotidase, 3′-nucleotidase or phosphodiesterase activity. 5′-nucleotidase isolated from Torpedo electric organ hydrolyzes UDP-glucose at 8% of the rate of AMP hydrolysis. The possible phylogenetic origin of vertebrate 5′-nucleotidase from multifunctional nucleotide hydrolases is discussed. [ABSTRACT FROM AUTHOR]

Electron microscopic observations showed that the fungal metabolite brefeldin A caused disassembly of the Golgi complex in human choriocarcinoma cells and accumulation of alkaline phosphatase (ALP) in the endoplasmic reticulum (ER) and nuclear envelope, where ALP was not apparently detectable in control cells. Pulse/chase experiments with [35S]methionine demonstrated that in the control cells, ALP synthesized as a 63-kDa precursor form was rapidly converted to a 66-kDa form, by processing of its N-linked oligosaccharides from the highmannose type to the complex type, which was expressed on the cell surface after 30 min of chase. In contrast, in the brefeldin-A-treated cells the precursor was gradually converted to a 65-kDa form, slightly smaller than the control mature form. which was not expressed on the cell surface even after a prolonged time of chase. Kinetics of the ALP processing in thc brefeldin-A-treated cells demonstrated that thc precursor was initially converted to an intermediate form, partially sensitive to endo-β-N-acetylglucosaminidase H (endo H), then to an endo-Hresistant 65-kDa form. In addition, this form was found to be sensitive to neuraminidase digestion, though its sialylation was not so complete as that of the control mature form. Taken together, these results suggest that under disassembly of the Golgi complex caused by brefeldin A, oligosaccharide-processing enzymes including sialyltransferase, an enzyme in the tram Golgi cisterna(e) and/or the frans Golgi network, might be redistributed into the ER and involved in processing of the oligosaccharides of ALP accumulating there. [ABSTRACT FROM AUTHOR]

A cDNA was cloned coding for human placental 5’-nucleotidase. The 3547-cDNA contains an open reading frame that encodes a 574-residue polypeptide with a calculated size of 63375 Da. The NH2-terminal 26 residues comprises a signal peptide, which is followed by the NH2-terminal sequence of the purified protein. Four potential N-linked glycosylation sites are found in the molecule, accounting for a larger mass of the mature form (71 kDa). The predicted structure contains a hydrophobic amino acid sequence at the COOH terminus, a possible signal for the post-translational modification by glycophosholipid. To confirm this possibility, we tried to isolate and characterize the membrane-anchoring domain of 5’-nucleotidase. BrCN-cleaved fragments of the protein were extracted with hexane and subjected to HPLC, resulting in purification of a single component of 2.3 kDa. Chemical analyses revealed that the purified fragment contains the tetradecapeptide Lys-Ile-Tyr-Pro-Ala-Val-Glu-Gly-Arg-Ile-Lys-Phe-Ser, ethanolamine, glucosamine, mannose, inositol, palmitic acid, and stearic acid. The peptide sequence determined is identified at positions 540-523 in the primary structure deduced from the cDNA sequence, which predicts a further extension to position 548, containing the hydrophobic amino acid sequence. Thus, it is concluded that the nmature 5’-nucleotidase lacks the predicted COOH-terminal peptide extension (524-548), which has been replaced by the glycophospholipid functioning as the membrane anchor of 5’-nucleotidase. [ABSTRACT FROM AUTHOR]

Structural analysis of 55 nearly full-length cDNA clones revealed heterogeneity in the 5'-untranslated regions of rat liver alkaline phosphatase mRNAs. The 5' extremities diverged into two totally unrelated sequence stretches at the position 88 nucleotides upstream of the initiation codon ATG. These two sequences, referred to as E1 and E2, were assigned on the genome about 36 000 base pairs (36 kbp) and 10 kbp upstream, respectively, of the exon coding for the 5'-most part of the common region. The gene consisted of 13 exons, including E1 and E2, and spanned about 56 kbp. The 11 exons (E3 to E13) following E1 and E2 were shared in common by the El-type and the E2-type mRNAs. Analyses by SI nuclease mapping and primer extension revealed the presence of two independent transcription-initiation sites specific to each of the El and E2 sequences. These results are interpreted as indicating a possible alternative usage of two leader exons, hence the presence of two independent promoters. Structural features of these putative promoters are described in the context of transcriptional fundamental and regulatory cis-elements. [ABSTRACT FROM AUTHOR]

We analyzed the asparagine-linked oligosaccharide chains of rat haptoglobin which were synthesized and secreted by hepatocytes in primary culture. When the cells were incubated with either [³H]mannose,[³H]galactose, or [³H]fucose, all the radioactive precursors were incorporated into the β subunit of haptoglobin. [³]HMannose-labled haptoglobin was purified from the culture medium by immunoaffinity chromatogrpahy, and [³H]oligosaccharides were prepared by strong alkali-borohydride treatment. The oligosccharides obtained were analyzed by anion-exchange high-performance liquid chromatography, concanavali-A - Sepharose chromatography and Bio-Gel P-4 chromatography before and after sequential exoglycosidase digestions. The oligosaccharides labeled with [³H]fucose or [³H]galactose were also characterized by the above methods. The results indicated that rat haptoglobin contains two complex-type oligosccharide chains in each β subunit one with a possible structure of (± NeuAc→Galβ→GlcNAcβ→)3(Manα→)2Manβ→GlcNAc→(±Fucα→)GcNAc and the other with (±NeuAc→Galβ→GlcNacβ→Manα→)2Manβ→GlcNAc→(±Fucα→)GlcNAc. [ABSTRACT FROM AUTHOR]

We have previously shown that the extracellular nucleoside triphosphate-hydrolyzing enzyme NTPDase2 is highly expressed in situ by stem/progenitor cells of the two neurogenic regions of the adult murine brain: the subventricular zone (type B cells) and the dentate gyrus of the hippocampus (residual radial glia). We explored the possibility that adult multipotent neural stem cells express nucleotide receptors and investigated their functional properties in vitro. Neurospheres cultured from the adult mouse SVZ in the presence of epidermal growth factor and fibroblast growth factor 2 expressed the ecto-nucleotidases NTPDase2 and the tissue non-specific isoform of alkaline phosphatase, hydrolyzing extracellular ATP to adenosine. ATP, ADP and, to a lesser extent, UTP evoked rapid Ca2+ transients in neurospheres that were exclusively mediated by the metabotropic P2Y1 and P2Y2 nucleotide receptors. In addition, agonists of these receptors and low concentrations of adenosine augmented cell proliferation in the presence of growth factors. Neurosphere cell proliferation was attenuated after application of the P2Y1-receptor antagonist MRS2179 and in neurospheres from P2Y1-receptor knockout mice. In situ hybridization identified P2Y1-receptor mRNA in clusters of SVZ cells. Our results infer nucleotide receptor-mediated synergism that augments growth factor-mediated cell proliferation. Together with the in situ data, this supports the notion that extracellular nucleotides contribute to the control of adult neurogenesis. [ABSTRACT FROM AUTHOR]