PPARβ/δ and PPARγ maintain undifferentiated phenotypes of mouse adult neural precursor cells from the subventricular zone.

Carolina Bernal,Verã³Nica Palma,Miguel Bronfman,Claudia Araya

doi:10.3389/fncel.2015.00078

Abstract

The subventricular zone (SVZ) is one of the main niches of neural stem cells in the adult mammalian brain. Stem and precursor cells in this region are the source for neurogenesis and oligodendrogesis, mainly in the olfactory bulb and corpus callosum, respectively. The identification of the molecular components regulating the decision of these cells to differentiate or maintain an undifferentiated state is important in order to understand the modulation of neurogenic processes in physiological and pathological conditions. PPARs are a group of transcription factors, activated by lipid ligands, with important functions in cellular differentiation and proliferation in several tissues. In this work, we demonstrate that mouse adult neural precursor cells (NPCs), in situ and in vitro, express PPARβ/δ and PPARγ. Pharmacological activation of both PPARs isoforms induces proliferation and maintenance of the undifferentiated phenotype. Congruently, inhibition of PPARβ/δ and PPARγ results in a decrease of proliferation and loss of the undifferentiated phenotype. Interestingly, PPARγ regulates the level of EGFR in adult NPCs, concurrent with it is function described in embryonic NPCs. Furthermore, we describe for the first time that PPARβ/δ regulates SOX2 level in adult NPCs, probably through a direct transcriptional regulation, as we identified two putative PPAR response elements in the promoter region of Sox2. EGFR and SOX2 are key players in neural stem/precursor cells self-renewal. Finally, rosiglitazone, a PPARγ ligand, increases PPARβ/δ level, suggesting a possible cooperation between these two PPARs in the control of cell fate behavior. Our work contributes to the understanding of the molecular mechanisms associated to neural cell fate decision and places PPARβ/δ and PPARγ as interesting new targets of modulation of mammalian brain homeostasis.

Highlights

The subventricular zone of the lateral ventricles (SVZ) in the adult mammalian brain is one of two major CNS neural stem cell niches
PPARβ/δ and PPARγ are Present in Mouse Adult SVZ neural precursor cells (NPCs) and Activities of these Receptors are Inducible by Exogenous Ligands In order to evaluate if PPARβ/δ and PPARγ are expressed in proliferating NPCs in the SVZ, adult mice were injected for 5 days intraperitoneally with BrdU followed by immunostaining on coronal brain sections
We observed that both PPARβ/δ and PPARγ are expressed in BrdU positive cells in the SVZ of adult mice, as detected by co-labeling with BrdU immunostaining (Figure 1A)

Summary

Introduction

The subventricular zone of the lateral ventricles (SVZ) in the adult mammalian brain is one of two major CNS neural stem cell niches. Among the molecules that regulate NPCs pool proliferation and maintenance, Sonic Hedgehog (Shh) and Epidermal Growth Factor (EGF) have been addressed as important mitogenic signals (Reynolds et al, 1992; Doetsch et al, 2002; Palma et al, 2005; Reinchisi et al, 2013; Alvarez-Buylla and Ihrie, 2014). Much progress has been made in understanding NPCs function in the adult brain, the detailed understanding of events regulating the delicate balance between self-renewal capacity and stem cell fate is still far from being clarified

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