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PubMed1997

The neuronal cell-adhesion molecule axonin-1 is specifically released by an endogenous glycosylphosphatidylinositol-specific phospholipase.

Axonin-1, a member of the immunoglobulin/fibronectin type-III family of cell-adhesion molecules, occurs both as a glycosylphosphatidylinositol-(glycosylPtdIns)-anchored membrane-bound and a soluble form. In vivo observations show that the major part of axonin-1 is found in the soluble fraction and that soluble axonin-1 perturbs neurite fasciculation and pathfinding in the developing chicken embryo. This has prompted further investigations into the mechanism of the axonin-1 release. We demonstrate here that axonin-1 released from dorsal root ganglion neurons contains ethanolamine and inositol, components of the glycosylPtdIns anchor. Secreted axonin-1 does not exhibit the cross-reacting determinant epitope, an indication that the cleavage of the anchor is not mediated by a phosphatidylinositol-specific phospholipase C. Treatment of dorsal root ganglion neurons with 1,10-phenanthroline, an inhibitor of glycosylPtdIns-specific phospholipase D, reduces the release of axonin-1 by 56%. Moreover, glycosylPtdIns-specific phospholipase D activity was detected in dorsal root ganglion neurons and brain. These results suggest that axonin-1 is released from the membrane by an endogenously expressed glycosylPtdIns-specific phospholipase D in vivo. With domain-swaping experiments between axonin-1 and its non-released relative F11, deletion mutants and monoclonal antibodies, we demonstrate that the fourth fibronectin type-III-like domain of axonin-1 is required for the generation of the soluble form of axonin-1.

Animals↗
PubMed1993

Cell-cell adhesion by homophilic interaction of the neuronal recognition molecule axonin-1.

The axonal surface glycoprotein axonin-1, which occurs both as a glycosyl-phosphatidylinositol-anchored membrane-bound form and a secreted form, promotes neurite outgrowth and is thought to be involved in axon-guidance mechanisms in the developing nervous system. Recently, we have demonstrated that the neurite-outgrowth-promoting activity of axonin-1, presented as a substratum for cultured neurons, is mediated by a heterophilic interaction with the axonal glycoprotein neuronglia cell-adhesion molecule (Ng-CAM). Here we present evidence for homophilic (like-like) binding among axonin-1 molecules. Axonin-1 was heterologously expressed in myeloma cells. Clonal cell lines, with exposed membrane-bound axonin-1 at their surface, formed large multicellular aggregates. Incubations of transfected and parental myeloma cells, under a series of different conditions, revealed homophilic axonin-1/axonin-1 interactions across the intermembrane space as the molecular mechanism promoting stable cell-cell contacts. Using structural and functional characterisation, recombinant axonin-1 was very similar to native axonin-1, suggesting that homophilic axonin-1 interactions are also established in neurons. The capability of axonin-1 to interact with both Ng-CAM and other axonin-1 molecules might contribute to the formation of macromolecular networks at contact sites of growth cones and axons, comprising molecules of both membranes, and thus represent a mechanism for regulating neurite outgrowth and pathfinding.

Animals↗
PubMed1993

Neuronal 'differentiation' of murine neuroblastoma cells induced by neocarzinostatin: neural cell adhesion molecules.

Neural crest tumor cells which have been pharmacologically induced in culture to undergo neuronal 'differentiation' have been proposed as a model for normal neural crest cell differentiation. We have previously reported that murine neuroblastoma cells treated with the antineoplastic agent neocarzinostatin (NCS) adopt the light microscopic appearance of differentiated neurons. After undergoing morphologic change, the cells no longer divide. As part of an effort to compare the process of differentiation in these cells with what is known about normal neural crest cells, we have examined the cellular distribution and isoform complement of neural cell adhesion molecules (NCAMs) in native and NCS-treated neuroblastoma cells. Our studies show that NCS induces profound changes in NCAM distribution. Immunohistochemical staining indicates that, in contrast to native neuroblastoma cells, more than 80% of treated cells display surface NCAM by 4 days following treatment. Unlike the case for normal neurons, NCAM is uniformly distributed over the treated cell surface. Neuroblastoma cells treated with NCS are more avidly adherent to culture plates coated with NCAM than are control neuroblastoma cells, reflecting the homophilic binding characteristics of NCAM. Interestingly, Western blot analysis for NCAM demonstrates similar total cellular content of a single NCAM species in both control and treated neuroblastoma cells. Furthermore, this 120 kDa mol. wt. NCAM is an isoform of NCAM not found on normally differentiated cerebellar neurons. While the presence of NCAM on these treated murine neuroblastoma cells is evidence for 'differentiation' along neuronal lines, the isoform complement and cell surface distribution of NCAM in treated cells are not normal.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Silencer elements modulate the expression of the gene for the neuron-glia cell adhesion molecule, Ng-CAM.

The combined factors that regulate the expression of cell adhesion molecules (CAMs) during development of the nervous system are largely unknown. To identify such factors for Ng-CAM, the neuron-glia CAM, constructs containing portions of the 5' end of the Ng-CAM gene were examined for activity after transfection into N2A neuroblastoma and NIH3T3 cells. Positive regulatory elements active in both cell types included an Ng-CAM proximal promoter with SP1 and cAMP response element motifs extending 447 base pairs upstream of a single RNA start site and a region within the first exon corresponding to 5'-untranslated sequences. Negative regulatory elements included five neuron-restrictive silencer elements (NRSEs) and a binding site for Pax gene products in a 305-base pair segment of the first intron. Constructs containing the promoter together with the entire first intron were active in N2A cells but were silenced in NIH3T3 cells. This silencer activity was mapped to the NRSEs. In contrast, the Pax motif inhibited activity of Ng-CAM constructs in both cell types. The DNA elements defined in these transfection experiments were examined for their ability to bind nuclear factors. The region within the first exon formed a DNA-protein complex after exposure to nuclear extracts prepared from both NIH3T3 and N2A cells. The NRSE region formed a more prominent complex with proteins prepared from NIH3T3 cells than it did with extracts from N2A cells. A member of the Pax protein family, Pax-3 bound to the Pax motif. Mutations introduced within the Pax motif in its ATTA sequence eliminated this binding whereas mutations in its GTTCC sequence did not, suggesting that paired homeodomain interactions are important for the recognition of Pax-3 by this DNA target sequence. The combined data suggest that negative regulation by NRSEs and Pax proteins may play a key role in the place-dependent expression patterns of Ng-CAM during development.

3T3 Cells↗
PubMed2005

Macrophage-induced inflammation affects hippocampal plasticity and neuronal development in a murine model of HIV-1 encephalitis.

Cognitive, behavioral, and motor impairments, during progressive human immunodeficiency virus type 1 (HIV-1) infection, are linked to activation of brain mononuclear phagocytes (MP; perivascular macrophages and microglia). Activated MPs effect a giant cell encephalitis and neuroinflammatory responses that are mirrored in severe combined immunodeficient (SCID) mice injected with human monocyte-derived macrophages (MDM). Whether activated human MDMs positioned in the basal ganglia affect hippocampal neuronal plasticity, the brain subregion involved in learning and memory, is unknown. Thus, immunohistochemical techniques were used for detection of newborn neurons (polysialylated neuronal cell adhesion molecule [PSA-NCAM]) and cell proliferation (Ki-67) to assay MDM effects on neuronal development in mouse models of HIV-1 encephalitis. Immunodeficient (C.B.-17/SCID and nonobese diabetic/SCID, NOD/SCID) and immune competent (C.B.-17) mice were injected with uninfected or HIV-1-infected MDM. Sham-operated or unmanipulated mice served as controls. Neuronal plasticity was evaluated in the hippocampal dentate gyrus (DG) at days 7 and 28. By day 7, increased numbers of Ki-67+ cells, PSA-NCAM+ cells and dendrites in DG were observed in sham-operated animals. In contrast, significant reductions in neuronal precursors and altered neuronal morphology paralleled increased microglial activation in both HIV-1-infected and uninfected MDM-injected animals. DG cellular composition was restored at day 28. We posit that activated MDM induce inflammation and diminish DG neuronal plasticity. These data provide novel explanations for the cognitive impairments manifested during advanced HIV-1 infection.

AIDS Dementia Complex↗
PubMed2002

Complementary expression and heterophilic interactions between IgLON family members neurotrimin and LAMP.

Neurotrimin (Ntm) and the limbic system-associated membrane protein (LAMP) are members of the IgLON (LAMP, OBCAM, Ntm) family of glycorylphosphatidylinositol anchored neural cell adhesion molecules. We previously reported that LAMP and Ntm promote adhesion and neurite outgrowth via a homophilic mechanism, suggesting that these proteins promote the formation of specific neuronal circuits by homophilic interactions. In this report, we have further characterized the expression and binding specificity of Ntm. Using a newly generated monoclonal antibody to Ntm, we demonstrated that this protein is largely expressed in a complementary pattern to that of LAMP in the nervous system, with co-expression at a few sites. Ntm is expressed at high levels in sensory-motor cortex and, of particular note, is transiently expressed in neurons of cortical barrel fields and corresponding thalamic "barreloids." Binding of a recombinant, soluble form of Ntm to CHO cells expressing either Ntm or LAMP demonstrates that Ntm and LAMP interact both homophilically and heterophilically. In contrast to conventional growth-promoting activity of Ig superfamily members, LAMP strongly inhibits the outgrowth of Ntm-expressing dorsal root ganglion (DRG) neurons in a heterophilic manner. These anatomical and functional data support the concept that homophilic and heterophilic interactions between IgLON family members are likely to play a role in the specification of neuronal projections via growth promoting and inhibiting effects, respectively.

Animals↗
PubMed2001

The polysialylated neural cell adhesion molecule reaches cell surfaces of hypothalamic neurons and astrocytes via the constitutive pathway.

Understanding how neurons and glia sort and deliver cell adhesion molecules to their cell surface should provide important clues as to how such molecules participate in dynamic neuronal functions in the developing and adult brain. The present study examines translocation of polysialylated neural cell adhesion molecule (PSA-NCAM), a negative regulator of cell adhesion, in cells of the rat hypothalamo-neurohypophysial system in which it is expressed throughout life and which undergo morphological remodelling in response to stimulation. PSA-NCAM expression in this system does not vary markedly in relation to different conditions of regulated neurosecretion, suggesting that the glycoprotein reaches cell surfaces via the constitutive pathway. To study this more directly, we here used immunofluorescence for PSA on NCAM in live, unpermeabilized cells to monitor PSA-NCAM surface expression in organotypic slice cultures from postnatal rat hypothalami. Subsequent immunolabelling for oxytocin confirmed that the cultures included magnocellular oxytocinergic neurons displaying many properties of adult neurosecretory neurons in situ. In the cultures, immunoreaction for PSA-NCAM was visible on the surface of oxytocinergic and non-oxytocinergic axons. This reaction disappeared after exposure of the cultures to endoneuraminidase, an enzyme which specifically cleaves alpha-2-8-linked PSA from NCAM. PSA-NCAM reappeared on axonal surfaces 4h after enzyme washout. Such reexpression was visibly not affected by neuronal activity inhibition (blockade of Ca(2+) channels with Mn(2+), of Na(+) channels with tetrodotoxin, or of glutamate receptors with 6-cyano-7-nitroquinoxaline-2,3-dione or D-2-amino-5-phosphonopentanoic acid) or facilitation (K(+) depolarization or GABA-A receptor blockade with bicuculline). In contrast, PSA-NCAM surface translocation was inhibited reversibly by cooling the cultures at 20 degrees C, a procedure which blocks constitutive secretion and which resulted in accumulation of PSA-NCAM in the cytoplasm of oxytocinergic and non-oxytocinergic neurons. This treatment also revealed PSA-NCAM in the cytoplasm of underlying astrocytes. Our observations provide direct evidence that PSA-NCAM reaches the cell surface of hypothalamic neurons and astrocytes via the constitutive pathway, independently of Ca(2+) entry and enhanced neuronal activity. Thus, PSA-NCAM in the hypothalamo-neurohypophysial system would be continuously available to permit its cells to undergo remodelling whenever the proper stimulus intervenes.

Animals↗
PubMed1993

Are the glypiated adhesion molecules preferentially targeted to the axonal compartment?

The question of how the cell surface molecules may be specifically delivered to subdomains of neurons is of particular interest considering that polarized sorting to the axon could enable adhesion glycoproteins to induce fasciculation of axonal tracts, guidance to the target cell, and the establishment of synaptic contacts. It was recently proposed that GPI-anchored molecules undergo preferential delivery to the axonal surface, implicating a similar polarized sorting of glycoproteins in neurons and epithelial cells (Dotti and Simons, 1990; Dotti et al., 1991). This review focuses on the cellular and subcellular localization of several glypiated adhesion molecules (Thy-1, TAG-1, F3/F11, P-31) in the developing and adult cerebellar cortex of the mouse. We conclude that the cellular distribution of GPI-anchored adhesion molecules within neurons is very complex and depends on: 1. The neuronal cell types, for example, F3/F11 is localized in axons in granule cells but is present in all compartments of Golgi cells. 2. The molecule itself: Thy-1, TAG-1, and P-31 are present on the granule cell body, whereas at the same developmental stage, F3/F11 is restricted to the axon. 3. The differentiation state: Thy-1 delivery to the axon correlates with postsynaptic target maturation.

Animals↗
PubMed1994

Isolation of granulosa-like cells from the bovine secretory corpus luteum and their characterization in long-term culture.

BACKGROUND: The isolation of cells termed type 5 from the bovine corpus luteum was recently reported. Since these cells were reminiscent of immature granulosa cells, their morphological and functional relationship requires further investigation in view of the novel concept of corpus luteum growth. It suggests that putative stem cells of unknown origin supply the pool of small luteal cells. METHODS: Bovine corpora lutea were mechanically dispersed, cell suspensions separated over a Percoll density gradient, and type 5 cells purified by colony transfer. Granulosa cells were harvested from small-sized antral follicles. Observations were carried out at the light and electron microscopical level. 3 beta-Hydroxy-steroid-dehydrogenase was localized histochemically in addition to intracellular lipid droplets stained with nile red. Immunolocalization was used to study Factor VIII antigen presence, the architecture of the cytoskeleton, as well as the occurrence of neuronal cell adhesion molecules, and of neuronal cadherin-like molecules. The uptake of acetylated low density lipoprotein was examined. As for progesterone concentration, cells were seeded at low density on day zero. Cell numbers and progesterone levels of supernatants were determined on day 10 in culture. RESULTS AND CONCLUSIONS: Type 5 cells behaved morphologically like immature granulosa cells, yet the total cell number and the progesterone concentration differed for type 5 cells compared to granulosa cells. The addition of LH had no influence on the progesterone concentration as seen for either type 5 cells or for granulosa cells. It is concluded that type 5 cells, which were originally mistaken for microvascular endothelial cells, display similarities with immature granulosa cells. Type 5 cells may play a role in renewal of luteal cells.

Animals↗
PubMed2002

Differential effects of unnatural sialic acids on the polysialylation of the neural cell adhesion molecule and neuronal behavior.

In this study we have examined how unnatural sialic acids can alter polysialic acid expression and influence the adhesive properties of the neural cell adhesion molecule (NCAM). Unnatural sialic acids are generated by metabolic conversion of synthetic N-acyl mannosamines and are typically incorporated into cell-surface glycoconjugates. However, N-butanoylmannosamine and N-pentanoylmannosamine are effective inhibitors of polysialic acid (PSA) synthesis in stably transfected HeLa cells expressing NCAM and the polysialyltransferase STX. These cells were used as substrates to examine the effect of inhibiting PSA synthesis on the development of neurons derived from the chick dorsal root ganglion. N-butanoylmannosamine blocked polysialylation of NCAM and significantly reduced neurite outgrowth comparable with enzymatic removal of PSA by endoneuraminidases. As a result, neurite outgrowth was similar to that observed for non-polysialylated NCAM. In contrast, previous studies have shown that N-propanoyl sialic acid (SiaProp), generated from N-propanoylmannosamine, is readily accepted by polysialyltransferases and permits the extension of poly(SiaProp) on NCAM. Despite being immunologically distinct, poly(SiaProp) can promote neurite outgrowth similarly to natural polysialic acid. Thus, subtle structural differences in PSA resulting from the incorporation of SiaProp residues do not alter the antiadhesive properties of polysialylated NCAM.

Acetylation↗
PubMed2006

Neural cell adhesion molecule (NCAM) induces neuronal phenotype acquisition in dominant negative MEK1-expressing hippocampal neural progenitor cells.

It has been shown that neural cell adhesion molecule (NCAM)-induced neuronal differentiation is extracellular signal-regulated kinase (ERK)-dependent. However, an involvement of the mitogen activated protein kinase (MAPK) kinase (MEK), an upstream kinase of ERK, has not been directly demonstrated in this process. Therefore, we investigated whether the MEK1 plays a critical role in the NCAM-induced neuronal differentiation of hippocampal neural progenitor cells (NPCs). NPCs were transiently transfected with expression plasmids encoding activated or dominant negative (DN) forms of MEK1. The expression of DN MEK1 inhibited neuronal phenotype acquisition and soluble NCAM rescued the defect in the neuronal phenotype acquisition in DN-MEK1-transfected cells, suggesting that NCAM might contribute to the neuronal differentiation via distinct, parallel pathways including the MEK pathway. In cells expressing wild type MEK1 or constitutively active MEK1 on the other hand, the percentage of cells positive for beta-tubulin type III (Tuj1), a marker for early postmitotic neurons, was higher than seen in vector-transfected cells. These results suggest that the activation of MEK1 is required for obtaining neuronal phenotype in NPCs.

Animals↗
PubMed1995

[Developmental mechanisms of neural network in the cerebellar system].

Various cell adhesion molecules and neurotrophic factors are involved in cell migration, axonal elongation and synaptogenesis during the development of neural networks. The developmental mechanisms of neural networks were investigated in the mouse cerebellar system in relation to the neuron-glia interactions and the expression of cell adhesion molecules. Radial migration of Purkinje cells in the cerebellar primordium is guided by contact with radial glial processes, and expression of the neuron-glia cell adhesion molecule tenascin is involved in this process. Purkinje cell migration is obstructed in the reeler mutant mouse, and the disorganized arrangement of radial glial processes is considered to be responsible for this defect. Pontine nuclei and inferior olivary nuclei constitute the cerebellar afferent system, and these neurons are generated from the rhombic lip which is originated from the alar plate of the metencephalon in common with the cerebellar primordium. Pontine nuclei migrate tangentially from the rhombic lip under the pia mater, and the binding sites for peanut lectin are specifically expressed on the migratory route. Thy-1 molecule, a member of the immunoglobulin superfamily is expressed transiently in the synaptogenesis between the cerebellar afferent fibers and their target neurons in the developing cerebellar cortex. The homophilic binding activity of this molecule is considered to be involved in the recognition between presynaptic terminals and postsynaptic structures.

Animals↗
PubMed1996

Distinct effects of recombinant tenascin-R domains in neuronal cell functions and identification of the domain interacting with the neuronal recognition molecule F3/11.

We have identified distinct domains of the rat extracellular matrix glycoprotein tenascin-R using recombinant fragments of the molecule that confer neuronal cell functions. In short-term adhesion assays (0.5 h), cerebellar neurons adhered best to the fragment representing the fibrinogen knob (FG), but also the fibronectin type III (FN) repeats 1-2 and 6-8. FG, FN1-2 and FN3-5 were the most repellent fragments for neuronal cell bodies. Neurites and growth cones were strongly repelled from areas coated with fragments containing the cysteine-rich stretch and the EGF-like domains (EGF-L), FN1-2, FN3-5 and FG. Polarization of morphology of hippocampal neurons was exclusively associated with FG, while EGF-L prevented neurite outgrowth altogether. The binding site of the neuronal receptor for tenascin-R, the immunoglobulin superfamily adhesion molecule F3/11, was localized to EGF-L. The combined observations show distinct, but also overlapping functions for the different tenascin-R domains. They further suggest the existence of multiple neuronal tenascin-R receptors which influence the response of neurons to their extracellular matrix environment.

Animals↗
PubMed2000

The third fibronectin type III repeat is required for L1 to serve as an optimal substratum for neurite extension.

As a means of defining functionally important regions of the L1 neuronal cell adhesion molecule, neurite outgrowth from cerebellar neurons was compared on monolayers of L1-negative B28 glioma cells, B28 cells transfected with wild-type human L1, and B28 cells transfected with variant forms of L1. Neurite outgrowth on L1-positive B28 cells is greatly enhanced over that seen on parental B28 cells. Neurite outgrowth on B28 cells expressing L1 variants that lack either the first or the fifth fibronectin type III repeat is comparable to that seen on monolayers expressing wild-type L1. In contrast, B28 cells expressing L1 without the third fibronectin type III repeat do not support neurite outgrowth above the background level seen on parental B28 cells. This suggests that the third fibronectin type III repeat plays a key role in the ability of L1 to promote neurite extension. This is consistent with reports that the third fibronectin type III repeat mediates L1 homomultimerization and integrin binding and that plasmin cleavage within this domain interferes with L1 function by abolishing these molecular interactions.

Amino Acid Sequence↗
PubMed1991

Neurite outgrowth in response to transfected N-CAM and N-cadherin reveals fundamental differences in neuronal responsiveness to CAMs.

Different neuronal populations were used to compare the neurite outgrowth-promoting activities of N-CAM and N-cadherin expressed via gene transfer on the surface of nonneuronal cells. In contrast to a previously reported developmental loss of retinal ganglion cell responsiveness to N-CAM, these cells exhibited an increased and maintained responsiveness to N-cadherin over the same developmental period (E6-E11). N-CAM and N-cadherin responses could be specifically inhibited by their own antibodies, but not by antisera to the beta 1 integrin family or the L1/G4 glycoprotein. Cerebellar neurons showed qualitative differences in the nature of the dose-response curves for transfected N-CAM expression (highly cooperative) versus N-cadherin expression (linear). In addition "subthreshold" levels of N-CAM expression, which do not normally support neurite outgrowth, did so when coexpressed with functional levels of N-cadherin. These studies show fundamental differences in neuronal responsiveness to cell adhesion molecules and suggest a more dynamic regulation for N-CAM-dependent neurite outgrowth than for N-cadherin-dependent outgrowth.

Animals↗
PubMed1998

Dissection of complex molecular interactions of neurofascin with axonin-1, F11, and tenascin-R, which promote attachment and neurite formation of tectal cells.

Neurofascin is a member of the L1 subgroup of the Ig superfamily that promotes axon outgrowth by interactions with neuronal NgCAM-related cell adhesion molecule (NrCAM). We used a combination of cellular binding assays and neurite outgrowth experiments to investigate mechanisms that might modulate the interactions of neurofascin. In addition to NrCAM, we here demonstrate that neurofascin also binds to the extracellular matrix glycoprotein tenascin-R (TN-R) and to the Ig superfamily members axonin-1 and F11. Isoforms of neurofascin that are generated by alternative splicing show different preferences in ligand binding. While interactions of neurofascin with F11 are only slightly modulated, binding to axonin-1 and TN-R is strongly regulated by alternatively spliced stretches located in the NH2-terminal half, and by the proline-alanine-threonine-rich segment. In vitro neurite outgrowth and cell attachment assays on a neurofascin-Fc substrate reveal a shift of cellular receptor usage from NrCAM to axonin-1, F11, and at least one additional protein in the presence of TN-R, presumably due to competition of the neurofascin- NrCAM interaction. Thereby, F11 binds to TN-R of the neurofascin/TN-R complex, but not to neurofascin, whereas axonin-1 is not able to bind directly to the neurofascin/TN-R complex as shown by competition binding assays. In conclusion, these investigations indicate that the molecular interactions of neurofascin are regulated at different levels, including alternative splicing and by the presence of interacting proteins.

Alternative Splicing↗
PubMed2004

Phospholipase D2 functions as a downstream signaling molecule of MAP kinase pathway in L1-stimulated neurite outgrowth of cerebellar granule neurons.

Stimulation of the neuronal cell adhesion molecule L1 in cerebellar granule neurons (CGNs) enhances neurite outgrowth and this response is inhibited by the primary alcohol ethanol. Because primary alcohols suppress the formation of the signaling lipid phosphatidic acid (PA) by phospholipase D (PLD), this observation prompted us to investigate whether PLD plays a role in the L1-mediated neurite outgrowth in CGNs. In the cerebellum of postnatal day 8 mice, PLD2 protein was abundantly expressed, while PLD1 expression was not detected. The L1-stimulated neurite outgrowth was inhibited by primary alcohols and by overexpression of lipase-deficient PLD2. Increases in cellular PA levels by direct PA application or overexpression of wild-type PLD2 mimicked the L1-dependent stimulation of neurite outgrowth. Furthermore, it was found that L1 stimulation in CGNs increased PLD activity concomitantly with phosphorylation of extracellular signal-regulated kinase (ERK), both of which were inhibited by the MAP kinase-ERK kinase (MEK) inhibitor. These results provide evidence that PLD2 functions as a downstream signaling molecule of ERK to mediate the L1-dependent neurite outgrowth of CGNs, a mechanism that may be related to alcohol-related neurodevelopmental disorders.

Alcohols↗