An Emerging Role of PRRT2 in Regulating Growth Cone Morphology.

Anna Corradi,Flavia Valtorta,Fabio Benfenati,Jin-Wu Tsai,Elisa Savino,Fabrizia Claudia Guarnieri

doi:10.3390/cells10102666

Abstract

Mutations in the PRRT2 gene are the main cause for a group of paroxysmal neurological diseases including paroxysmal kinesigenic dyskinesia, episodic ataxia, benign familial infantile seizures, and hemiplegic migraine. In the mature central nervous system, the protein has both a functional and a structural role at the synapse. Indeed, PRRT2 participates in the regulation of neurotransmitter release, as well as of actin cytoskeleton dynamics during synaptogenesis. Here, we show a role of the protein also during early stages of neuronal development. We found that PRRT2 accumulates at the growth cone in cultured hippocampal neurons. Overexpression of the protein causes an increase in the size and the morphological complexity of growth cones. In contrast, the growth cones of neurons derived from PRRT2 KO mice are smaller and less elaborated. Finally, we demonstrated that the aberrant shape of PRRT2 KO growth cones is associated with a selective alteration of the growth cone actin cytoskeleton. Our data support a key role of PRRT2 in the regulation of growth cone morphology during neuronal development.

Highlights

Mutations in the PRRT2 gene cause a broad spectrum of paroxysmal neurological diseases including paroxysmal kinesigenic dyskinesia, episodic ataxia, benign familial infantile seizures, and hemiplegic migraine [1]
PRRT2 Was Expressed in the Growth Cones of Developing Neurons
Cues involved in this guidance include chemotropic gradients and specific extracellular matrix substrates that, once interacting with their corresponding growth cone receptors, induce cytoskeletal reorganisation, leading to a modification of the shape and to a redirection of the extending growth cone [18]

Summary

Introduction

Mutations in the PRRT2 gene cause a broad spectrum of paroxysmal neurological diseases including paroxysmal kinesigenic dyskinesia, episodic ataxia, benign familial infantile seizures, and hemiplegic migraine [1]. Biallelic loss of PRRT2 results in more severe phenotypes with developmental delay and cognitive difficulties [2], suggesting a functional role of the protein during neurodevelopmental events. PRRT2 was found among the proteins enriched in axonal growth cones of developing cortical neurons [5]. We described a structural role for PRRT2, involving a link with the dynamic changes in the actin cytoskeleton which occur during the process of synaptogenesis [7]. These findings raise the possibility that PRRT2 plays a role in the early stages of neuronal development, in which actin dynamics play a critical role

Methods

Results

Conclusion