EphA4 Regulates Neuroblast and Astrocyte Organization in a Neurogenic Niche

Abstract

Significant migration cues are required to guide and contain newly generated rodent subventricular zone (SVZ) neuroblasts as they transit along the lateral ventricles and then through the anterior forebrain to their ultimate site of differentiation in the olfactory bulbs (OBs). These cues enforce strict neuroblast spatial boundaries within the dense astroglial meshwork of the SVZ and rostral migratory stream (RMS), yet are permissive to large-scale neuroblast migration. Therefore, the molecular mechanisms that define these cues and control dynamic interactions between migratory neuroblasts and surrounding astrocytes are of particular interest. We found that deletion of EphA4 and specifically ablation of EphA4 kinase activity resulted in misaligned neuroblasts and disorganized astrocytes in the RMS/SVZ, linking EphA4 forward signaling to SVZ and RMS spatial organization, orientation, and regulation. In addition, within a 3 week period, there was a significant reduction in the number of neuroblasts that reached the OB and integrated into the periglomerular layer, revealing a crucial role for EphA4 in facilitating efficient neuroblast migration to the OB. Single-cell analysis revealed that EPHA4 and its EFN binding partners are expressed by subpopulations of neuroblasts and astrocytes within the SVZ/RMS/OB system resulting in a cell-specific mosaic, suggesting complex EphA4 signaling involving both homotypic and heterotypic cell-cell interactions. Together, our studies reveal a novel molecular mechanism involving EphA4 signaling that functions in stem cell niche organization and ultimately neuroblast migration in the anterior forebrain.

OTX2 signals from the choroid plexus to regulate adult neurogenesis

“…Robo2 is strongly expressed in RMS astrocytes and is required for proper RMS organization and guidance of neuroblasts (Kaneko et al, 2010), and it has been hypothesized that astrocyte-derived laminin helps form RMS scaffold for neuroblast migration (Belvindrah et al, 2007). Also, EphA4 and EphrinA2 are expressed in RMS and V-SVZ supporting astrocytes (along with other combinations of Ephs and Ephrins) and EPHA4 has been shown to be critical for maintaining a compact and organized RMS (Todd et al, 2017). While OTX2 has been shown to bind Robo2 promoter (Hoch et al, 2015) and to regulate Ephrin-A2 (Rhinn et al, 1999), we did not detect any changes in V-SVZ expression after OTX2 knock-down.…”

“…Several receptors and factors are expressed in V-SVZ and RMS astrocytes that could potentially alter microenvironment composition and signaling. These include extracellular matrix (ECM) proteins such as thrombospondin (Thbs1 and Thbs4) and tenascin-C (Tnc) (Jankovski and Sotelo, 1996;Girard et al, 2014) and signaling molecules such as Robo and Eph receptors along with Ephrin ligands (Kaneko et al, 2010;Ming and Song, 2011;Falcão et al, 2012;Gengatharan et al, 2016;Todd et al, 2017), which may be under transcriptional control of OTX2 (Gherzi et al, 1997;Boncinelli and Morgan, 2001;Hoch et al, 2015;Peña et al, 2017). Expression analysis on V-SVZ microdissection lysates from the scFv-Otx2 non-cell autonomous OTX2 knock-down model showed that EphrinA1, Thbs1, Thbs4 and Tnc were upregulated in V-SVZ ( Fig.…”

Apoptosis-Induced Wnt2/β-Catenin Signaling Triggers Astrocytic Dedifferentiation and Facilitates Neurogenesis in Ischemic Cortex

“…Previous studies have reported the migration of new-born neuroblasts, although very weak, from the SVZ to the cortex after ischemia [18,19]. Considering that astrocytes in the SVZ play important roles for maintaining the neurognic niche [20], we hypothesized that these Nestin-positive reactive astrocytes might provide supporting signals for neurogenesis in ischemic cortex. We then investigated the effects of Wnt2 knockdown on the post-ischemic cortical neurogenesis.…”

Possible role of EphA4 and VEGFR2 interactions in neural stem and progenitor cell differentiation

“…Ligand interaction with the cell membrane is through glycosyl phosphatidylinositol linkage for ephrin-As, and through a short cytoplasmic and transmembrane domain for ephrin-Bs. EphA4-mediated forward signaling regulates neuroblast and astrocyte organization in a neurogenic niche (10). EphA4 may protect against neuronal loss and reverse cellular aging (5).…”