Extracellular Control of Radial Glia Proliferation and Scaffolding During Cortical Development and Pathology

Abstract

During the development of the cortex, newly generated neurons migrate long-distances in the expanding tissue to reach their final positions. Pyramidal neurons are produced from dorsal progenitors, e.g., radial glia (RGs) in the ventricular zone, and then migrate along RG processes basally toward the cortex. These neurons are hence dependent upon RG extensions to support their migration from apical to basal regions. Several studies have investigated how intracellular determinants are required for RG polarity and subsequent formation and maintenance of their processes. Fewer studies have identified the influence of the extracellular environment on this architecture. This review will focus on extracellular factors which influence RG morphology and pyramidal neuronal migration during normal development and their perturbations in pathology. During cortical development, RGs are present in different strategic positions: apical RGs (aRGs) have their cell bodies located in the ventricular zone with an apical process contacting the ventricle, while they also have a basal process extending radially to reach the pial surface of the cortex. This particular conformation allows aRGs to be exposed to long range and short range signaling cues, whereas basal RGs (bRGs, also known as outer RGs, oRGs) have their cell bodies located throughout the cortical wall, limiting their access to ventricular factors. Long range signals impacting aRGs include secreted molecules present in the embryonic cerebrospinal fluid (e.g., Neuregulin, EGF, FGF, Wnt, BMP). Secreted molecules also contribute to the extracellular matrix (fibronectin, laminin, reelin). Classical short range factors include cell to cell signaling, adhesion molecules and mechano-transduction mechanisms (e.g., TAG1, Notch, cadherins, mechanical tension). Changes in one or several of these components influencing the RG extracellular environment can disrupt the development or maintenance of RG architecture on which neuronal migration relies, leading to a range of cortical malformations. First, we will detail the known long range signaling cues impacting RG. Then, we will review how short range cell contacts are also important to instruct the RG framework. Understanding how RG processes are structured by their environment to maintain and support radial migration is a critical part of the investigation of neurodevelopmental disorders.

Keywords: apical radial glia; cell signaling; cell-cell interaction; cortical development; extracellular matrix; neuronal migration; scaffold.

FIGURE 1

Radial glias function as both the source and the support of newborn neurons in the developing cortex. Apical radial glia (aRG) extend an apical process reaching the ventricular surface, where they expose their primary cilia, as well as a basal process reaching the cortical surface. Basal radial glia (bRG) have their cell bodies located in more basal areas of the cortical wall. Apical and basal processes from these cells (blue) establish the scaffold across the whole cortical wall. RGs undergo cell division, giving birth to a daughter cell which can be either another RG (apical or basal – symmetric division) or a basal progenitor (asymmetric division, intermediate progenitors are represented in orange). These cells give rise to migrating neuroblasts (green) which move along RG basal processes to reach their final position within the cortical layers. First deep layer neurons are generated, then upper layer neurons are born.

FIGURE 2

Extracellular factors controling the scaffolding of RGs. RGs are exposed to a variety of extracellular cues. These signals can be secreted molecules (blue boxes) or received directly from other cells (green boxes). In apical regions aRGs receive signals from the eCSF as their cell bodies and primary cilia are in contact with the ventricles. They also establish contacts between themselves and with the extracellular matrix (ECM). In basal regions, RG basal processes are exposed to secreted cues from the meninges and from already differentiated neurons. These interactions can occur while neurons are migrating along them. Basal processes also exhibit interactions between themselves.

FIGURE 3

Remote extracellular factors controling the scaffolding of RGs. Some of the extracellular cues controlling RG development are produced and secreted from relatively remote locations. Here are represented the factors present in the CSF (upper schema) which are detailed in this review, namely FGF2, EGF, IGF, BDNF, BMPs, WNT, SHH, and TGF- β1. On the bottom schema, extracellular cues derived from the meninges and acting on the extremities of basal processes are depicted, namely, laminin, collagen, neuregulins and retinoid acid. Cajal Retzius cells (in purple) are migrating cells which in early stages of development tangentially move in the MZ of the developing cortex. These cells are a source of Reelin amongst other molecules which influence RG scaffolding.

FIGURE 4

Molecular pathways triggered by eCSF-derived factors. The growth factors found in the eCSF are mainly known to trigger the mitogen-activated protein kinases (MAPK) pathway (also known as the RAS-RAF-MEK-ERK pathway). This molecular signaling pathway is involved in the regulation of several essential cellular processes such as proliferation, differentiation, survival and death. BMP receptors (BMPR) activate the phosphorylation of SMAD1/5, which can activate directly transcription of target genes or act via the translocation of YAP into the nucleus. WNT molecules activate the Frizzled receptors and LRP6 co-receptors which will allow Disheveled (DVL) to inhibit the Axin-APC complex. This complex is a major inhibitor of β-catenin. Therefore, upon WNT activation, β-catenin is free to be directed into the nucleus to activate its target genes. Finally SHH binds to its receptor Patched1 (Ptch1), which then releases the 7 transmembrane protein Smoothened (Smo) from its inhibition. Smo activation triggers the cleavage of Gli transcription factors into their active form (GliA). GliA is then enriched in the nucleus to allow transcription of target genes (such as Cyclin D1 or Gli itself).

FIGURE 5

Close range contacts controling the scaffolding of RGs. RGs directly receive signals from neighboring cells such as other RGs or migrating neurons. On the top panel are depicted the cell–cell interactions occurring at the apical side of aRGs. Adherens junctions between aRGs are crucial for the maintenance of the scaffold. In the enlarged box is represented the binding of N-cadherins which can link extracellular contacts with the cytoskeleton (via Plekha7 or β-catenin) or with polarity proteins such as Par3, Par6, and PKC. On the bottom panel is illustrated basal cell–cell interactions. Basal processes of RGs can interact with each other inducing a Cdc42 response intracellularly. Neurons can also directly act on the glial scaffold by secreting factors such as GGF which controls growth and maintenance of basal processes. Finally, basal processes receive information from the extracellular matrix, especially via the interaction between intergins and laminins.