Interplay in neural functions of cell adhesion molecule close homolog of L1 (CHL1) and Programmed Cell Death 6 (PDCD6).
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ABSTRACT:
SUBMITTER: Loers G
PROVIDER: S-EPMC8728108 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Upregulation of expression of the close homolog of adhesion molecule L1 (CHL1) by reactive astrocytes in the glial scar reduces axonal regeneration and inhibits functional recovery after spinal cord injury (SCI). Here, we investigate the molecular mechanisms underlying upregulation of CHL1 expression by analyzing the signal transduction pathways in vitro. We show that astrogliosis stimulated by bacterial lipopolysaccharide (LPS) upregulates CHL1 expression in primary cultures of mouse cerebral astrocytes, coinciding with elevated protein synthesis and translocation of protein kinase delta (PKCdelta) from cytosol to the membrane fraction. Blocking PKCdelta activity pharmacologically and genetically attenuates LPS-induced elevation of CHL1 protein expression through a phosphatidylinositol 3-kinase (PI3K) dependent pathway. LPS induces extracellular signal-regulated kinases (ERK1/2) phosphorylation through PKCdelta and blockade of ERK1/2 activation abolishes upregulation of CHL1 expression. LPS-triggered upregulation of CHL1 expression mediated through translocation of nuclear factor kappaB (NF-kappaB) to the nucleus is blocked by a specific NF-kappaB inhibitor and by inhibition of PI3K, PKCdelta, and ERK1/2 activities, implicating NF-kappaB as a downstream target for upregulation of CHL1 expression. Furthermore, the LPS-mediated upregulation of CHL1 expression by reactive astrocytes is inhibitory for hippocampal neurite outgrowth in cocultures. Although the LPS-triggered NO-guanylate cyclase-cGMP pathway upregulates glial fibrillary acid protein expression in cultured astrocytes, we did not observe this pathway to mediate LPS-induced upregulation of CHL1 expression. Our results indicate that elevated CHL1 expression by reactive astrocytes requires activation of PI3K/PKCdelta-dependent pathways and suggest that reduction of PI3K/PKCdelta activity represents a therapeutic target to downregulate CHL1 expression and thus benefit axonal regeneration after SCI.
| S-EPMC2795071 | biostudies-literature
Project description:The close homolog of L1 (CHL1) is a cell adhesion molecule involved in regulation of neuronal differentiation and survival, neurite outgrowth and axon guidance during development. In the mature nervous system, CHL1 regulates synaptic activity and plasticity. The aim of the present study was to evaluate the influence of CHL1 on peripheral nerve regeneration after trauma. Using the established model of mouse femoral nerve regeneration, CHL1 knock-out mice were investigated in comparison to the wild type littermates. First, non-injured mice of both genotypes were compared regarding the synaptic phenotypes in the corresponding spinal cord segment. While no differences in phenotypes were detectable in the femoral nerve, corresponding segments in the spinal cord were observed to differ in that inhibitory perisomatic innervation of motor neurons was increased in CHL1-deficient mice, and numbers of perisomatic cholinergic synapses on motor neuronal somata were reduced. Regarding the femoral nerve after injury, CHL1-deficient mice demonstrated preferential motor axon regrowth into the saphenous vs. quadriceps branch after nerve transection upstream of the nerve bifurcation by 8 weeks after transection, indicating decreased preferential motor re-innervation. Furthermore, in injured wild-type mice, enhanced CHL1 expression was observed in regenerating axons in the proximal nerve stump upstream of the bifurcation at days 1, 3, 5, 7 and 14, and in the distal stump at days 7 and 14 after injury, when compared to non-injured mice. Injury-related upregulation of CHL1 expression was more pronounced in axons than in Schwann cells. Despite a more pronounced capacity for preferential motor axon regrowth in wild-type vs. mutant mice, only a tendency for difference in recovery of motor functions was observed between genotypes, without statistical significance Taken together, these results indicate that CHL1 is involved in peripheral nerve regeneration, because it guides regrowing axons into the appropriate nerve branch and regulates synaptic coverage in the spinal cord.
| S-EPMC5976800 | biostudies-literature
Project description:Cell recognition molecules are involved in nervous system development and participate in synaptic plasticity in the adult brain. The close homolog of L1 (CHL1), a recently identified member of the L1 family of cell adhesion molecules, is expressed by neurons and glia in the central nervous system and by Schwann cells in the peripheral nervous system in a pattern overlapping, but distinct from, the other members of the L1 family. In humans, CHL1 (also referred to as CALL) is a candidate gene for 3p- syndrome-associated mental impairment. In the present study, we generated and analyzed CHL1-deficient mice. At the morphological level, these mice showed alterations of hippocampal mossy fiber organization and of olfactory axon projections. Expression of the mRNA of the synapse-specific neural cell adhesion molecule 180 isoform was upregulated in adult CHL1-deficient mice, but the mRNA levels of several other recognition molecules were not changed. The behavior of CHL1-deficient mice in the open field, the elevated plus maze, and the Morris water maze indicated that the mutant animals reacted differently to their environment. Our data show that the permanent absence of CHL1 results in misguided axonal projections and aberrant axonal connectivity and alters the exploratory behavior in novel environments, suggesting deficits in information processing in CHL1-deficient mice.
| S-EPMC134725 | biostudies-literature
Project description:The ?-site amyloid precursor protein-cleaving enzyme BACE1 is a prime drug target for Alzheimer disease. However, the function and the physiological substrates of BACE1 remain largely unknown. In this work, we took a quantitative proteomic approach to analyze the secretome of primary neurons after acute BACE1 inhibition, and we identified several novel substrate candidates for BACE1. Many of these molecules are involved in neuronal network formation in the developing nervous system. We selected the adhesion molecules L1 and CHL1, which are crucial for axonal guidance and maintenance of neural circuits, for further validation as BACE1 substrates. Using both genetic BACE1 knock-out and acute pharmacological BACE1 inhibition in mice and cell cultures, we show that L1 and CHL1 are cleaved by BACE1 under physiological conditions. The BACE1 cleavage sites at the membrane-proximal regions of L1 (between Tyr(1086) and Glu(1087)) and CHL1 (between Gln(1061) and Asp(1062)) were determined by mass spectrometry. This work provides molecular insights into the function and the pathways in which BACE1 is involved, and it will help to predict or interpret possible side effects of BACE1 inhibitor drugs in current clinical trials.
| S-EPMC3406677 | biostudies-literature
Project description:INTRODUCTION:Diagnosis of gastrointestinal stroma tumors (GIST) is based on the histological evaluation of tissue specimens. Reliable systemic biomarkers are lacking. We investigated the local expression of the neural cell adhesion molecule L1-like protein (CHL1) in GIST and determined whether soluble CHL1 proteoforms could serve as systemic biomarkers. MATERIAL AND METHODS:Expression of CHL1 was analyzed in primary tumor specimens and metastases. 58 GIST specimens were immunohistochemically stained for CHL1 on a tissue microarray (TMA). Systemic CHL1 levels were measured in sera derived from 102 GIST patients and 91 healthy controls by ELISA. Results were statistically correlated with clinicopathological parameters. RESULTS:CHL1 expression was detected in GIST specimens. Reduced tissue expression was significantly associated with advanced UICC stages (p = 0.036) and unfavorable tumor localization (p = 0.001). CHL1 serum levels are significantly elevated in GIST patients (p < 0.010). Elevated CHL1 levels were significantly associated with larger tumors (p = 0.023), advanced UICC stage (p = 0.021), and an increased Fletcher score (p = 0.041). Moreover, patients with a higher CHL1 serum levels displayed a significantly shortened recurrence free survival independent of other clinicopathological variables. CONCLUSION:Local CHL1 expression and serum CHL1 levels show a reverse prognostic behavior, highlighting the relevance of proteolytic shedding of the molecule. The results of the study indicate a potential role of serum CHL1 as a diagnostic and prognostic marker in GIST.
| S-EPMC7138165 | biostudies-literature
Project description:Close homologue of L1 (CHL1) is a transmembrane cell adhesion molecule that is critical for brain development and for the maintenance of neural circuits in adults. Recent studies revealed that CHL1 has diverse roles and is involved in the regulation of recovery after spinal cord injury. CHL1 expression was downregulated in the cerebral cortex, hypothalamus, and brain stem after the induction of acute hypoxia (AH). In the current study, we sought to address the role of CHL1 in regulating homeostasis responses to hypoxia using CHL1-knockout (CHL1(-/-)) mice. We found that, compared with wild-type littermates, CHL1(-/-) mice showed a dramatically lower mortality rate and an augmented ventilatory response after they were subjected to AH. Immunofluorescence staining revealed that CHL1 was expressed in the carotid body (CB), the key oxygen sensor in rodents, and CHL1 expression level in the CB as assayed by western blot was decreased after hypoxic exposure. The number of glomus cells and the expression of tyrosine hydroxylase (a marker for glomus cells) in the CB of CHL1(-/-) mice appeared to be increased compared with CHL1(+/+) mice. In addition, in the ex vivo CB preparation, hypoxia induced a significantly greater afferent nerve discharge in CHL1(-/-) mice compared with CHL1(+/+) mice. Furthermore, the arterial blood pressure and plasma catecholamine levels of CHL1(-/-) mice were also significantly higher than those of CHL1(+/+) mice. Our findings first demonstrate that CHL1 is a novel intrinsic factor that is involved in CB function and in the ventilatory response to AH.
| S-EPMC3763446 | biostudies-literature
Project description:Abnormal development of ventral midbrain (VM) dopaminergic (DA) pathways, essential for motor and cognitive function, may underpin a number of neurological disorders and thereby highlight the importance of understanding the birth and connectivity of the associated neurons. While a number of regulators of VM DA neurogenesis are known, processes involved in later developmental events, including terminal differentiation and axon morphogenesis, are less well understood. Recent transcriptional analysis studies of the developing VM identified genes expressed during these stages, including the cell adhesion molecule with homology to L1 (Chl1). Here, we map the temporal and spatial expression of CHL1 and assess functional roles of substrate-bound and soluble-forms of the protein during VM DA development. Results showed early CHL1 in the VM, corresponding with roles in DA progenitor migration and differentiation. Subsequently, we demonstrated roles for CHL1 in both axonal extension and repulsion, selectively of DA neurons, suggestive of a role in guidance towards forebrain targets and away from hindbrain nuclei. In part, CHL1 mediates these roles through homophilic CHL1-CHL1 interactions. Collectively, these findings enhance our knowledge of VM DA pathways development, and may provide new insights into understanding DA developmental conditions such as autism spectrum disorders.
| S-EPMC5570898 | biostudies-literature
Project description:The neural cell adhesion molecule L1 participates in homophilic interactions important for axon guidance and neuronal development. The structural details of homophilic adhesion mediated by L1 and other immunoglobulin superfamily members containing an N-terminal horseshoe arrangement of four immunoglobulin-like domains are unknown. Here we used cryo-electron tomography to study liposomes to which intact or truncated forms of the L1 ectodomain were attached. Tomographic reconstructions revealed an adhesion interface with a regular and repeating pattern consistent with interactions between paired horseshoes contributed by L1 proteins from neighboring liposomes. The characteristics of the pattern changed when N-linked carbohydrates were altered by removing sialic acids or converting from complex to high mannose or oligomannose glycans, suggesting a regulatory role for carbohydrates in L1-mediated homophilic adhesion. Using the results from tomograms and crystal structures of L1-related molecules, we present a structural model for L1-mediated homophilic adhesion that depends on protein-protein, protein-carbohydrate, and carbohydrate-carbohydrate interactions.
| S-EPMC2744468 | biostudies-literature
Project description:Prenatal ethanol exposure causes fetal alcohol spectrum disorders (FASD) in part by disrupting the neural cell adhesion molecule L1. L1 gene mutations cause neuropathological abnormalities similar to those of FASD. Ethanol and 1-butanol inhibit L1-mediated cell-cell adhesion (L1 adhesion), whereas 1-octanol antagonizes this action. To test the hypothesis that there are alcohol binding sites on L1, we used 3-azibutanol and 3-azioctanol, the photoactivatable analogs of 1-butanol and 1-octanol, to photolabel the purified Ig1-4 domain of human L1 (hL1 Ig1-4). 3-Azibutanol (11 mM), like ethanol, inhibited L1 adhesion in NIH/3T3 cells stably transfected with hL1, whereas subanesthetic concentrations of 3-azioctanol (14 microM) antagonized ethanol inhibition of L1 adhesion. 3-Azibutanol (100-1,000 microM) and 3-azioctanol (10-100 microM) photoincorporated into Tyr-418 on Ig4 and into two adjacent regions in the N terminus, Glu-33 and Glu-24 to Glu-27. A homology model of hL1 Ig1-4 (residues 33-422), based on the structure of the Ig1-4 domains of axonin-1, suggests that Glu-33 and Tyr-418 hydrogen-bond at the interface of Ig1 and Ig4 to stabilize a horseshoe conformation of L1 that favors homophilic binding. Furthermore, this alcohol binding pocket lies within 7 A of Leu-120 and Gly-121, residues in which missense mutations cause neurological disorders similar to FASD. These data suggest that ethanol or selected mutations produce neuropathological abnormalities by disrupting the domain interface between Ig1 and Ig4. Characterization of alcohol agonist and antagonist binding sites on L1 will aid in understanding the molecular basis for FASD and might accelerate the development of ethanol antagonists.
| S-EPMC2224219 | biostudies-other
Project description:BACKGROUND: The neural cell adhesion molecule L1 plays a crucial role in development and plasticity of the nervous system. Neural cells thus require precise control of L1 expression. RESULTS: We identified a full binding site for nuclear factor I (NFI) transcription factors in the regulatory region of the mouse L1 gene. Electrophoretic mobility shift assay (EMSA) showed binding of nuclear factor I-A (NFI-A) to this site. Moreover, for a brain-specific isoform of NFI-A (NFI-A bs), we confirmed the interaction in vivo using chromatin immunoprecipitation (ChIP). Reporter gene assays showed that in neuroblastoma cells, overexpression of NFI-A bs repressed L1 expression threefold. CONCLUSION: Our findings suggest that NFI-A, in particular its brain-specific isoform, represses L1 gene expression, and might act as a second silencer of L1 in addition to the neural restrictive silencer factor (NRSF).
| S-EPMC2805660 | biostudies-literature