Latent process genes for cell differentiation are common decoders of neurite extension length

Abstract

SummaryA latent process involving signal transduction and gene expression is needed as a preparation step for cellular function. We previously found that nerve growth factor (NGF)-induced cell differentiation has a latent process, which is dependent on ERK activity and gene expression and required for subsequent neurite extension. A latent process can be considered as a preparation step that decodes extracellular stimulus information into cellular functions; however, molecular mechanisms of this process remain unknown. We identified Metrnl, Dclk1 and Serpinb1a as genes that are induced during the latent process (LP) with distinct temporal expression profiles and are required for subsequent neurite extension in PC12 cells. The LP genes showed distinct dependency on the duration of ERK activity, and they were also induced during the latent process of PACAP-and forskolin-induced cell differentiation. Regardless of neurotrophic factors, expression levels of the LP genes during the latent process (0-12 hours), but not phosphorylation levels of ERK, always correlated with subsequent neurite extension length (12-24 hours). Overexpression of all LP genes together, but not of each gene separately, enhanced NGF-induced neurite extension. The LP gene products showed distinct spatial localization. Thus, the LP genes appear to be the common decoders for neurite extension length regardless of neurotrophic factors, and they might function in distinct temporal and spatial manners during the latent process. Our findings provide molecular insight into the physiological meaning of the latent process as the preparation step for decoding information for future phenotypic change.

Induction of serpinb1a by PACAP or NGF is required for PC12 cells survival after serum withdrawal

“…The fact that multiple transduction pathways promote serpinb1a expression suggests that this gene could be involved in several cellular functions. Nevertheless, investigations achieved by using siRNA revealed that in contrast to what has recently been reported by Watanabe and collaborators (Watanabe et al 2012), in our hands serpinb1a inhibition with two different siRNA does not affect the ability of PACAP or NGF to promote neuritogenesis, induce growth arrest, or increase cell size. In contrast, it appeared that blockade of serpinb1a expression suppressed the ability of PACAP and NGF to inhibit caspases-3/7 activity.…”

Integrative analysis of miRNA and mRNA expression profiles in pheochromocytoma and paraganglioma identifies genotype-specific markers and potentially regulated pathways

“…In cells capable of neuronal differentiation, such as PC12 cell, stimulation with NGF initiates a signal cascade that culminates in the transcriptional activation/repression of targets, as well as posttranslational modification of the activity for already present proteins (Watanabe et al 2012). According to our results, the overexpression of miR-183 and/or miR-96 in PC12 cells possibly downregulates genes induced by NGF stimulation necessary for neuronal differentiation.…”

Small molecule kinase inhibitor LRRK2-IN-1 demonstrates potent activity against colorectal and pancreatic cancer through inhibition of doublecortin-like kinase 1

“…U0126 was developed as an inhibitor of MEK1/2 but has also been shown to inhibit MAPK7 [24]. Moreover, it was previously reported that U0126 suppresses upregulation of DCLK1 in response to NGF stimulation in PC12 cells [25] and a search of the NCBI gene expression omnibus database produced multiple datasets demonstrating significant DCLK1 downregulation following U0126 inhibition in colon cancer cell lines (Figure  4D & Additional file 1: Figure S2F) [26,27]. As predicted, DCLK1 mRNA levels were decreased after 10 μM U0126 treatment (Figure  4E).…”