LPA-primed astrocytes induce axonal outgrowth of cortical progenitors by activating PKA signaling pathways and modulating extracellular matrix proteins.

Tania Cristina Leite De Sampaio E Spohr Spohr,Flã¡Via Carvalho Alcantara Gomes,Stevens Kastrup Rehen,Rã´Mulo Sperduto Dezonne

doi:10.3389/fncel.2014.00296

Tania Cristina Leite De Sampaio E Spohr Spohr, Flã¡Via Carvalho Alcantara Gomes + Show 2 more

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https://doi.org/10.3389/fncel.2014.00296

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Abstract

Lysophosphatidic acid (LPA) is one of the main membrane-derived lysophospholipids, inducing diverse cellular responses like cell proliferation, cell death inhibition, and cytoskeletal rearrangement, and thus is important in many biological processes. In the central nervous system (CNS), post-mitotic neurons release LPA extracellularly whereas astrocytes do not. Astrocytes play a key role in brain development and pathology, producing various cytokines, chemokines, growth factors, and extracellular matrix (ECM) components that act as molecular coordinators of neuron–glia communication. However, many molecular mechanisms underlying these events remain unclear—in particular, how the multifaceted interplay between the signaling pathways regulated by lysophospholipids is integrated in the complex nature of the CNS. Previously we showed that LPA-primed astrocytes induce neuronal commitment by activating LPA1–LPA2 receptors. Further, we revealed that these events were mediated by modulation and organization of laminin levels by astrocytes, through the induction of the epidermal growth factor receptor (EGFR) signaling pathway and the activation of the mitogen-activated protein (MAP) kinase (MAPK) cascade in response to LPA (Spohr et al., 2008, 2011). In the present work, we aimed to answer whether LPA affects astrocytic production and rearrangement of fibronectin, and to investigate the mechanisms involved in neuronal differentiation and maturation of cortical neurons induced by LPA-primed astrocytes. We show that PKA activation is required for LPA-primed astrocytes to induce neurite outgrowth and neuronal maturation and to rearrange and enhance the production of fibronectin and laminin. We propose a potential mechanism by which neurons and astrocytes communicate, as well as how such interactions drive cellular events such as neurite outgrowth, cell fate commitment, and maturation.

Highlights

Lysophospholipids (LPs) are structural components of cellular membranes and biologically active molecules
Lysophosphatidic acid (LPA)-PRIMED ASTROCYTES INDUCE FIBRONECTIN REARRANGEMENT To investigate whether fibronectin extracellular matrix (ECM) was modulated by astrocytes, we treated it with LPA for 4 h or with conditioned medium of LPA-treated astrocytes (LPA-Conditioned medium (CM)) for 24 h
In the present work, we investigated whether LPA stimulates astrocytes to rearrange and produce fibronectin and, if so, how this process affects neuronal differentiation and maturation

Summary

Introduction

Lysophospholipids (LPs) are structural components of cellular membranes and biologically active molecules. Lysophosphatidic acid (LPA) is one of the main membranederived LPs. Lysophosphatidic acid signaling properties are mediated by at least six G protein-coupled receptors, referred to as LPAR1–LPAR5 and P2Y5 (Gardell et al, 2006; Choi et al, 2010). Lysophosphatidic acid-induced cellular responses include cell proliferation, cell death inhibition, and cytoskeletal rearrangement, which play important roles in many biological processes such as oncogenesis, wound healing, immune functions, and especially brain development (Anliker and Chun, 2004; Choi et al, 2010). Lysophosphatidic acid receptors are expressed in subsets of cells in the developing and mature rodent nervous system and play key functions in its morphogenesis

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