TGF-β Superfamily Gene Expression and Induction of the Runx1 Transcription Factor in Adult Neurogenic Regions after Brain Injury

Trevor T Logan,Sonia Villapol,Aviva J Symes,Jialin Charles Zheng

doi:10.1371/journal.pone.0059250

Trevor T Logan, Sonia Villapol + Show 2 more

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https://doi.org/10.1371/journal.pone.0059250

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Abstract

Traumatic brain injury (TBI) increases neurogenesis in the forebrain subventricular zone (SVZ) and the hippocampal dentate gyrus (DG). Transforming growth factor-β (TGF-β) superfamily cytokines are important regulators of adult neurogenesis, but their involvement in the regulation of this process after brain injury is unclear. We subjected adult mice to controlled cortical impact (CCI) injury, and isolated RNA from the SVZ and DG at different post-injury time points. qPCR array analysis showed that cortical injury caused significant alterations in the mRNA expression of components and targets of the TGF-β, BMP, and activin signaling pathways in the SVZ and DG after injury, suggesting that these pathways could regulate post-injury neurogenesis. In both neurogenic regions, the injury also induced expression of Runt-related transcription factor-1 (Runx1), which can interact with intracellular TGF-β Smad signaling pathways. CCI injury strongly induced Runx1 expression in activated and proliferating microglial cells throughout the neurogenic regions. Runx1 protein was also expressed in a subset of Nestin- and GFAP-expressing putative neural stem or progenitor cells in the DG and SVZ after injury. In the DG only, these Runx1+ progenitors proliferated. Our data suggest potential roles for Runx1 in the processes of microglial cell activation and proliferation and in neural stem cell proliferation after TBI.

Highlights

Adult traumatic brain injury (TBI) is a prevalent injury that often results in permanent loss of neurological function
In this paper we demonstrate that cortical impact (CCI) increases the expression of Transforming growth factor-b (TGF-b) and bone morphogenetic proteins (BMPs) cytokines in neurogenic regions in adult mice for up to a week after TBI
We show that Runx1 is an early injury-induced transcription factor expressed in both microglia and neural stem cell (NSC) in the adult neurogenic niches

Summary

Introduction

Adult traumatic brain injury (TBI) is a prevalent injury that often results in permanent loss of neurological function. Treatments which help regenerate neurons could be beneficial, and significant recent research has focused on the possibility that the endogenous neural stem cell (NSC) population could be harnessed to stimulate regeneration and recovery of the central nervous system (CNS) following injury [5,6]. Widespread inflammation occurs concomitantly with cell death after injury, with microglia and astrocytes becoming activated and blood borne immune cells entering the lesion. This post-injury inflammation has broad impact on processes in both the lesion area and the neurogenic regions [7,8,9]

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