Lysophosphatidic Acid Receptor 1 Specifically Labels Seizure-Induced Hippocampal Reactive Neural Stem Cells and Regulates Their Division

Abstract

A population of neural stem cells (NSCs) dwelling in the dentate gyrus (DG) is able to generate neurons throughout adult life in the hippocampus of most mammals. These NSCs generate also astrocytes naturally and are capable of generating oligodendrocytes after gene manipulation. It has been more recently shown that adult hippocampal NSCs after epileptic seizures as well as subventricular zone NSCs after stroke can give rise to reactive astrocytes (RAs). In the hippocampus, the induction of seizures triggers the conversion of NSCs into reactive NSCs (React-NSCs) characterized by a drastic morphological transformation, abnormal migration, and massive activation or entry into the cell cycle to generate more React-NSCs that ultimately differentiate into RAs. In the search for tools to investigate the properties of React-NSCs, we have explored the LPA 1-green fluorescent protein (GFP) transgenic line of mice in which hippocampal NSCs are specifically labeled due to the expression of lysophosphatidic acid receptor 1 (LPA 1). We first addressed the validity of the transgene expression as true marker of LPA 1 expression and then demonstrated how, after seizures, LPA 1-GFP labeled exclusively React-NSCs for several weeks. Then React-NSCs lost LPA 1-GFP expression as neurons of the granule cell layer started to express it. Finally, we used knockout for LPA 1 transgenic mice to show that LPA 1 plays a functional role in the activation of React-NSCs. Thus, we confirmed that LPA 1-GFP expression is a valid tool to study both NSCs and React-NSCs and that the LPA 1 pathway could be a target in the intent to preserve NSCs after seizures.

Survival of Stem Cells and Progenitors in the Intestine Is Regulated by LPA5-Dependent Signaling

“…13 The effects of LPA are mediated through 6 distinct LPA receptors (LPARs), termed LPA 1 -LPA 6 (gene names Lpar1-Lpar6), which activate major cellular signaling pathways, including the Wnt, phosphoinositide 3-kinase (PI3K), and epidermal growth factor (EGF) pathways. 13 The expression of LPAR in embryonic stem cells 14,15 and neural stem cells, 16,17 along with the effects of LPA on neural development 18 and myeloid differentiation, 19 has been reported. A recent study using mouse enteroids showed that LPA can be used instead of EGF to support enteroid growth.…”

HB-EGF and zinc activate EGFR to induce reactive neural stem cells in the mouse hippocampus after seizures

“…The reactive astrocyte-like morphology typical of the seizure-induced React-NSCs (Sierra et al, 2015b; Muro-García et al, 2019; Valcárcel-Martín et al, 2020) was reduced and NSCs looked closer to normal conserving their radial morphology in the MTLE-HS mice treated with gefitinib. To quantify this effect, we analyzed Nestin-GFP+ cells by Sholl analysis and measured the overall process length, the cell volume and ramification as branch points (Figure 3F, 3G and 3H, respectively).…”

“…In parallel to alterations in neurogenesis, seizures trigger astrogliogenesis in the DG. We have recently characterized using mouse models of MTLE-HS, how seizures induce the transformation of hippocampal NSCs into reactive NSCs (React-NSCs) who contribute to HS through the direct generation of reactive astrocytes at the expense of neurogenesis (Sierra et al, 2015a; Muro-García et al, 2019; Valcárcel-Martín et al, 2020).…”

The transcription factor LEF1 interacts with NFIX and switches isoforms during adult hippocampal neural stem cell quiescence

“…NSPCs can be isolated from the adult hippocampal DG taking advantage of LPA 1 -GFP transgenic mice, yet only a subset of the precursors are proliferative cells based on the surface expression of other markers such as EGFR and Prominin-1. The remainder (majority) of LPA 1 -GFP are classified as nonproliferative or quiescent precursor cells (Walker et al, 2016;Valcárcel-Martín et al, 2020), so it is tempting to speculate that LEF1 may be involved in maintaining the expression of Lpar1 in quiescent NSPCs. Finally, it is worth to note that the Martynoga et al (2013) study (on which the analysis of LEF1 binding sites in enhancers is based) was performed in mouse NSPCs expanded in FGF2 and EGF, while our study employed rat NSPCs expanded in FGF2 only.…”