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Cadherin-12 regulates neurite outgrowth through PKA/Rac1/Cdc42 pathway in cortical neurons

ABSTRACT: Cadherins play an important role in tissue homeostasis, as they are responsible for cell-cell adhesion during embryogenesis, tissue morphogenesis, and differentiation. In this study, we identified Cadherin-12 (CDH12), which encodes a type II classical cadherin, as a gene to promote neurite outgrowth in a vitro model consist of neurons with differentiated intrinsic growth ability. First, the effects of CDH12 on neurons were evaluated by RNA interference, and the result indicated that the knock down of CDH12 expression restrained the axon extension of E18 neurons. The transcriptome profile of the neurons with or without siCDH12 treatment revealed a set of pathways positively correlated with the effect of CDH12 on neurite outgrowth. We further revealed that CDH12 affected Rac1/Cdc42 phosphorylation in PKA dependent manner by testing with H-89 and 8-Bromo-cAMP sodium salt. Moreover, we investigated the expression of CDH12 in brain, spinal cord, and dorsal root ganglion during development by using immunofluorescence staining. Thereafter, we explored the effects of CDH12 on neurite outgrowth in vivo. A zebrafish model of CDH12 knockdown was established by using NgAgo-gDNA system and registered the vital role of CDH12 in peripheral neurogenesis. In summary, our study is the first to report the effect of CDH12 on axonal extension in vitro and in vivo and we provided a preliminary explanation for the mechanism.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE183174 | GEO | 2021/12/09

REPOSITORIES: GEO

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Project description:We have undertaken a genome-wide study of transcriptional activity in embryonic superior cervical ganglia (SCG) and dorsal root ganglia (DRG) during a time course of neurite outgrowth in vitro. Gene expression observed in these models likely includes both developmental gene expression patterns and regenerative responses to axotomy, which occurs as the result of tissue dissection. Comparison across both models revealed many genes with similar gene expression patterns during neurite outgrowth. These patterns were minimally affected by exposure to the potent inhibitory cue Semaphorin3A, indicating that this extrinsic cue does not exert major effects at the level of nuclear transcription. We also compared our data to several published studies of DRG and SCG gene expression in animal models of regeneration, and found the expression of a large number of genes in common between neurite outgrowth in vitro and regeneration in vivo. Experiment Overall Design: We wished to determine the transcriptional profiles of neurons undergoing neurite outgrowth in vitro. We were particularly interested in finding genes whose expression is generally associated with the process of neurite outgrowth, rather than with cell type-specific effects. Thus, in order to avoid focusing on transcripts unique to one tissue type versus another, we used a comparative strategy to look for effects that were common to two tissue types and therefore more likely to be involved in the general process of neurite outgrowth. While these explants contain multiple cell types, we felt this was preferable to the more disruptive conditions required to dissociate neurons or obtain a pure neuron population. To this end, we monitored gene expression in cultured explants from SCG and DRG using DNA microarrays. We initiated our studies by culturing embryonic day 13 (E13) mouse SCG in vitro and harvesting tissue for RNA isolation at time points from 2 to 65 hours. Time points were selected to detect both fast, short-term responses (2, 5 and 12 hours), as well as sustained, long-term changes (24, 40, and 65 hours). Samples were hybridized to Affymetrix MG-U74v2 A and B microarrays, with RNA from acutely dissected explants serving as a baseline reference. We followed these experiments with a parallel analysis of a more heterogeneous tissue type, the DRG, which is more frequently used than SCG for in vivo studies of neurite regeneration. Cervical and upper thoracic DRG from E12 embryos were cultured with NGF (the same trophic support as in SCG cultures), harvested at time points from 2 to 40 hours, and hybridized to Affymetrix MOE 430A microarrays.

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Cadherin-12 regulates neurite outgrowth through PKA/Rac1/Cdc42 pathway in cortical neurons

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