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Interplay in neural functions of cell adhesion molecule close homolog of L1 (CHL1) and Programmed Cell Death 6 (PDCD6).

ABSTRACT: Close homolog of L1 (CHL1) is a cell adhesion molecule of the immunoglobulin superfamily. It promotes neuritogenesis and survival of neurons in vitro. In vivo, CHL1 promotes nervous system development, regeneration after trauma, and synaptic function and plasticity. We identified programmed cell death 6 (PDCD6) as a novel binding partner of the CHL1 intracellular domain (CHL1-ICD). Co-immunoprecipitation, pull-down assay with CHL1-ICD, and proximity ligation in cerebellum and pons of 3-day-old and 6-month-old mice, as well as in cultured cerebellar granule neurons and cortical astrocytes indicate an association between PDCD6 and CHL1. The Ca²⁺-chelator BAPTA-AM inhibited the association between CHL1 and PDCD6. The treatment of cerebellar granule neurons with a cell-penetrating peptide comprising the cell surface proximal 30 N-terminal amino acids of CHL1-ICD inhibited the association between CHL1 and PDCD6 and PDCD6- and CHL1-triggered neuronal survival. These results suggest that PDCD6 contributes to CHL1 functions in the nervous system.

SUBMITTER: Loers G

PROVIDER: S-EPMC8728108 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Interplay in neural functions of cell adhesion molecule close homolog of L1 (CHL1) and Programmed Cell Death 6 (PDCD6).

Loers Gabriele G Theis Thomas T Baixia Hao Helen H Kleene Ralf R Arsha Sanjana S Samuel Nina N Arsha Neha N Young Wise W Schachner Melitta M

FASEB bioAdvances 20211103 1

Close homolog of L1 (CHL1) is a cell adhesion molecule of the immunoglobulin superfamily. It promotes neuritogenesis and survival of neurons in vitro. In vivo, CHL1 promotes nervous system development, regeneration after trauma, and synaptic function and plasticity. We identified programmed cell death 6 (PDCD6) as a novel binding partner of the CHL1 intracellular domain (CHL1-ICD). Co-immunoprecipitation, pull-down assay with CHL1-ICD, and proximity ligation in cerebellum and pons of 3-day-old a ...[more]

PMID: 35024572

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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.

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.

Dataset Information

Interplay in neural functions of cell adhesion molecule close homolog of L1 (CHL1) and Programmed Cell Death 6 (PDCD6).

Publications

Interplay in neural functions of cell adhesion molecule close homolog of L1 (CHL1) and Programmed Cell Death 6 (PDCD6).

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