Brief Report: Robo1 Regulates the Migration of Human Subventricular Zone Neural Progenitor Cells During Development

Abstract

SUMMARY Human neural progenitor cell (NPC) migration within the subventricular zone (SVZ) of the lateral ganglionic eminence is an active process throughout early brain development. The migration of human NPCs from the SVZ to the olfactory bulb during fetal stages resembles what occurs in adult rodents. As the human brain develops during infancy, this migratory stream is drastically reduced in cell number and becomes barely evident in adults. The mechanisms regulating human NPC migration are unknown. The Slit-Robo signaling pathway has been defined as a chemorepulsive cue involved in axon guidance and neuroblast migration in rodents. Slit and Robo proteins expressed in the rodent brain help guide neuroblast migration from the subventricular zone (SVZ) through the rostral migratory stream to the olfactory bulb. Here, we present the first study on the role that Slit and Robo proteins play in human-derived fetal neural progenitor cell migration (hfNPC). We describe that Robo1 and Robo2 isoforms are expressed in the human fetal SVZ. Furthermore, we demonstrate that Slit2 is able to induce a chemorepellent effect on the migration of hfNPCs derived from the human fetal SVZ. In addition, when Robo1 expression is inhibited, hfNPCs are unable to migrate to the olfactory bulb of mice when injected in the anterior SVZ. Our findings indicate that the migration of human NPCs from the SVZ is partially regulated by the Slit-Robo axis. This pathway could be regulated to direct the migration of NPCs in human endogenous neural cell therapy.

Human circular RNA‑0054633 regulates high glucose‑induced vascular endothelial cell dysfunction through the microRNA‑218/roundabout 1 and microRNA‑218/heme oxygenase‑1 axes

“…The current study also identified that the expression of miR-218 was able to inhibit the high glucose-induced HUVEc proliferation, migration and angiogenesis by targeting ROBO1 and HO-1. A previous study verified that the high expression levels of ROBO1 and HO-1 were able to significantly increase cell migration, proliferation and angiogenesis (17,18,39). Herein, it was also observed that the expression of VEGF was increased in high glucose conditions.…”

Cancer-selective nanoparticles for combinatorial siRNA delivery to primary human GBM in vitro and in vivo

“…Primary fetal neural progenitor cells (NPCs) were utilized as a healthy brain tissue control in order to assess the cell type specificity of siRNA delivery via R646. [16,17,49] NPCs are obtained as described previously following procedures approved by the Johns Hopkins University Institutional Review Board. [50] NPCs 34, 54, and 61, with each number indicating different tissue samples, were used to provide three separate cell source samples.…”

“…[15] siRNA is promising as a therapeutic to treat brain cancer for several reasons: i) it can hit targets that are seen as "undruggable" by conventional medicinal approaches; ii) it has the potential of overcoming drug resistances by affecting multiple disease-causing biochemical pathways in parallel; iii) it does not necessarily require reformulation of a drug delivery particle when the type of siRNA cargo changes; and, unlike DNA, iv) it does not risk introducing inheritable genetic changes. Protein targets of particular interest to us include Roundabout homolog 1 (Robol), a protein identified as key to normal and cancer cell migration; [16][17][18] yes-associated protein 1 (YAP1), which promotes growth of GBM cells; [19,20] sodium-potassium-chloride cotransporter (NKCC1), an ion transporter that affects cancer cell migration; [21,22] survivin, an anti-apoptotic gene whose expression in GBM correlates with proliferation [23] and with poor prognosis; [24] and endothelial growth factor receptor (EGFR), an oncogene whose aberrant expression is among the most common mutations in GBM. [25][26][27] Other reports of knockdown of Robo1, [18] YAP1, [28] NKCC1, [21,29] survivin, [30] or EGFR [31] often focus on knockdown of a single gene to isolate cellular mechanisms of GBM survival, growth, and invasion.…”

Human Cerebrospinal Fluid Modulates Pathways Promoting Glioblastoma Malignancy

“…The SVZ is the largest neurogenic niche in adults and is highly regulated by the flow of cerebrospinal fluid (CSF). The CSF milieu has the properties to sustain the neurogenic niche environment, regulating neural stem cells proliferation, differentiation, and migration (13,(16)(17)(18). Given the neurogenic potential that CSF holds on NSCs and the similarities between NSCs and BTICs, we explored the possibility that CSF might similarly affect GBM proliferation, differentiation, and migration.…”