Inhibition of Nischarin Expression Promotes Neurite Outgrowth through Regulation of PAK Activity.

Yuemin Ding,Linlin Wang,Ruyi Zhang,Yuying Li,Xiong Zhang,Linghui Zeng,Lingchao Lu,Ed Manser

doi:10.1371/journal.pone.0144948

Yuemin Ding, Linlin Wang + Show 6 more

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https://doi.org/10.1371/journal.pone.0144948

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Abstract

Nischarin is a cytoplasmic protein expressed in various organs that plays an inhibitory role in cell migration and invasion and the carcinogenesis of breast cancer cells. We previously reported that Nischarin is highly expressed in neuronal cell lines and is differentially expressed in the brain tissue of adult rats. However, the physiological function of Nischarin in neural cells remains unknown. Here, we show that Nischarin is expressed in rat primary cortical neurons but not in astrocytes. Nischarin is localized around the nucleus and dendrites. Using shRNA to knockdown the expression of endogenous Nischarin significantly increases the percentage of neurite-bearing cells, remarkably increases neurite length, and accelerates neurite extension in neuronal cells. Silencing Nischarin expression also promotes dendrite elongation in rat cortical neurons where Nischarin interacts with p21-activated kinase 1/2 (PAK1/2) and negatively regulates phosphorylation of both PAK1 and PAK2. The stimulation of neurite growth observed in cells with decreased levels of Nischarin is partially abolished by IPA3-mediated inhibition of PAK1 activity. Our findings indicate that endogenous Nischarin inhibits neurite outgrowth by blocking PAK1 activation in neurons.

Highlights

The outgrowth of neurites from neurons during development or following an injury is controlled by both extra- and intra-cellular molecules [1]
The findings indicated that interaction between Nischarin and PAK1 or PAK2 could happen at endogenous protein levels
We previously investigated the distribution of Nischarin in the rat brain and found that it is highly expressed in the mature neurons, whereas it is poorly expressed in the hippocampal DG region and the olfactory bulb, where the new-born cells exist [19]

Summary

Introduction

The outgrowth of neurites from neurons during development or following an injury is controlled by both extra- and intra-cellular molecules [1]. These molecules eventually converge onto the growth cone cytoskeleton, where there is coordinated cross-talk between actin filaments and microtubules [2]. Many cytoskeleton-associated proteins regulate cytoskeletal remodeling within axons [3]. Their function is controlled by the activation or inhibition of particular signaling pathways, such as the Rho-GTPases (guanosine triphosphatases) pathway. The Rho family of small GTPases, such as RhoA (Ras homologous member A), Rac (Rasrelated C3 botulinum toxin substrate 1), and Cdc (cell division cycle 42), act as molecular.

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