Migratory Cues Research Articles

Antigen-presenting ILC3 regulate T cell-dependent IgA responses to colonic mucosal bacteria.

Intestinal immune homeostasis is dependent upon tightly regulated and dynamic host interactions with the commensal microbiota. Immunoglobulin A (IgA) produced by mucosal B cells dictates the composition of commensal bacteria residing within the intestine. While emerging evidence suggests the majority of IgA is produced innately and may be polyreactive, mucosal-dwelling species can also elicit IgA via T cell-dependent mechanisms. However, the mechanisms that modulate the magnitude and quality of T cell-dependent IgA responses remain incompletely understood. Here we demonstrate that group 3 innate lymphoid cells (ILC3) regulate steady state interactions between T follicular helper cells (TfH) and B cells to limit mucosal IgA responses. ILC3 used conserved migratory cues to establish residence within the interfollicular regions of the intestinal draining lymph nodes, where they act to limit TfH responses and B cell class switching through antigen presentation. The absence of ILC3-intrinsic antigen presentation resulted in increased and selective IgA coating of bacteria residing within the colonic mucosa. Together these findings implicate lymph node resident, antigen-presenting ILC3 as a critical regulatory checkpoint in the generation of T cell-dependent colonic IgA and suggest ILC3 act to maintain tissue homeostasis and mutualism with the mucosal-dwelling commensal microbiota.

Production of Germ-Line Chimeras in Zebrafish.

The induction of germ-line chimerism in fish is a strategy for the reproduction of endangered or genetically valuable fish species. Chimeras can be created by transplanting a single primordial germ cell or multiple blastomeres from a donor into a sterile host embryo. When the host reaches sexual maturity, it will produce donor-originating gametes throughout its reproductive life span. This technique provides unique experimental conditions for basic biology research in model fish species like zebrafish. The success of cell transplantation relies on the effective sterilization of host embryos, the correct identification of developing germ cells, and the synchronization of migratory cues between the host and the transplanted cells. Developments in non-transgenic methods of germ cell ablation and identification have made germ cell transplantation more applicable to use in conservation and aquaculture. In this chapter, we provide a protocol for germ cell labeling by injection of chimeric RNA or FITC-dextran, the sterilization of host embryos using an antisense morpholino oligonucleotide, and two methods for producing germ-line chimeras in zebrafish: single primordial germ cell transplant and blastomere transplant.

Brief Exposure of Skin to Near-Infrared Laser Modulates Mast Cell Function and Augments the Immune Response.

The treatment of skin with a low-power continuous-wave (CW) near-infrared (NIR) laser prior to vaccination is an emerging strategy to augment the immune response to intradermal vaccine, potentially substituting for chemical adjuvant, which has been linked to adverse effects of vaccines. This approach proved to be low cost, simple, small, and readily translatable compared with the previously explored pulsed-wave medical lasers. However, little is known on the mode of laser-tissue interaction eliciting the adjuvant effect. In this study, we sought to identify the pathways leading to the immunological events by examining the alteration of responses resulting from genetic ablation of innate subsets including mast cells and specific dendritic cell populations in an established model of intradermal vaccination and analyzing functional changes of skin microcirculation upon the CW NIR laser treatment in mice. We found that a CW NIR laser transiently stimulates mast cells via generation of reactive oxygen species, establishes an immunostimulatory milieu in the exposed tissue, and provides migration cues for dermal CD103+ dendritic cells without inducing prolonged inflammation, ultimately augmenting the adaptive immune response. These results indicate that use of an NIR laser with distinct wavelength and power is a safe and effective tool to reproducibly modulate innate programs in skin. These mechanistic findings would accelerate the clinical translation of this technology and warrant further explorations into the broader application of NIR lasers to the treatment of immune-related skin diseases.

Materials Science and Design Principles of Growth Factor Delivery Systems in Tissue Engineering and Regenerative Medicine.

Growth factors (GFs) are signaling molecules that direct cell development by providing biochemical cues for stem cell proliferation, migration, and differentiation. GFs play a key role in tissue regeneration, but one major limitation of GF-based therapies is dosage-related adverse effects. Additionally, the clinical applications and efficacy of GFs are significantly affected by the efficiency of delivery systems and other pharmacokinetic factors. Hence, it is crucial to design delivery systems that provide optimal activity, stability, and tunable delivery for GFs. Understanding the physicochemical properties of the GFs and the biomaterials utilized for the development of biomimetic GF delivery systems is critical for GF-based regeneration. Many different delivery systems have been developed to achieve tunable delivery kinetics for single or multiple GFs. The identification of ideal biomaterials with tunable properties for spatiotemporal delivery of GFs is still challenging. This review characterizes the types, properties, and functions of GFs, the materials science of widely used biomaterials, and various GF loading strategies to comprehensively summarize the current delivery systems for tunable spatiotemporal delivery of GFs aimed for tissue regeneration applications. This review concludes by discussing fundamental design principles for GF delivery vehicles based on the interactive physicochemical properties of the proteins and biomaterials.

Coho Salmon Colonization of Oregon's Upper Willamette River Basin

Coho Salmon Oncorhynchus kisutch were historically absent from a major Columbia River subbasin, the upper Willamette River (UWR), until a fishway was installed at Willamette Falls and a sustained stocking program was implemented in the 1950s. Despite decades of stocking from three diverse source populations (early run, late run, and coastal Coho Salmon) during the second half of the twentieth century, adult abundance above the falls was less than 1,000 annually during the 1990s. A recent surge (>25,000 adults in 2009) has raised concerns about potential interactions with two native anadromous salmonids listed under the U.S. Endangered Species Act: UWR winter-run steelhead O. mykiss and UWR spring-run Chinook Salmon O. tshawytscha. We analyzed Coho Salmon stocking records and estimates of abundance from 1954–2017 to summarize population history, demographics, and adult phenology. We also characterized current Coho Salmon distribution using radiotelemetry (n = 219 adults in 2014) and evaluated potential mechanisms associated with changes in adult abundance. We identified a shift in adult migration timing over the time series that was consistent with an increase in late-run traits and environmental changes affecting migration cues. The distribution of radio-tagged adults among UWR subbasins was only weakly correlated with past stocking efforts, suggesting that habitat conditions, stocked phenotype, adaptation and range expansion by descendants of the relict stocked populations, or colonization from regional source populations strongly influenced current subpopulation abundance. Annual counts of returning UWR Coho Salmon were positively correlated with counts of Columbia River Coho salmon, suggesting a shared response to freshwater habitat or ocean conditions. Regardless of the underlying mechanisms affecting UWR Coho Salmon distribution and population size, the results illustrate the complex dynamics between changing landscapes and migration corridors, the introduction of nonnative species for harvest management goals, and the potential for nonnative fish to affect the conservation of native populations.

Effects of natal water dilution on the migration of Pacific salmon in a regulated river

AbstractAdult salmon are guided by chemical cues from their natal water during the spawning migration. Consequently, hydroelectric activities can have negative effects on adult salmon navigation if they alter the chemical properties of the homing environment. We conducted riverside experiments to examine the effects of natal water dilution resulting from hydroelectric operations on upstream navigation in a British Columbia river and the efficacy of current dilution management in providing clear migratory cues for two local populations of sockeye salmon (Oncorhynchus nerka) and a population of pink salmon (Oncorhynchus gorbuscha). We found that both sockeye populations exhibited behavioural preferences for pure natal water when compared with various levels of diluted natal water, whereas pink salmon, which spawn throughout the system and exhibit lower levels of natal site fidelity, appeared unaffected by natal water dilution. Our findings confirmed that current management operations were appropriate for ensuring timely migration to spawning grounds and highlight the potential effects of alterations to water odour properties on salmon migrations.

Fatty-acid derivative acts as a sea lamprey migratory pheromone

Olfactory cues provide critical information for spatial orientation of fish, especially in the context of anadromous migrations. Born in freshwater, juveniles of anadromous fish descend to the ocean where they grow into adults before migrating back into freshwater to spawn. The reproductive migrants, therefore, are under selective pressures to locate streams optimal for offspring survival. Many anadromous fish use olfactory cues to orient toward suitable streams. However, no behaviorally active compounds have been identified as migratory cues. Extensive studies have shown that the migratory adult sea lampreys (Petromyzon marinus), a jawless fish, track a pheromone emitted by their stream-dwelling larvae, and, consequently, enter streams with abundant larvae. We fractionated extracts of larval sea lamprey washings with guidance from a bioassay that measures in-stream migratory behaviors of adults and identified four dihydroxylated tetrahydrofuran fatty acids, of which (+)-(2S,3S,5R)-tetrahydro-3-hydroxy-5-[(1R)-1-hydroxyhexyl]-2-furanoctanoic acid was shown as a migratory pheromone. The chemical structure was elucidated by spectroscopies and confirmed by chemical synthesis and X-ray crystallography. The four fatty acids were isomer-specific and enantiomer-specific in their olfactory and behavioral activities. A synthetic copy of the identified pheromone was a potent stimulant of the adult olfactory epithelium, and, at 5 × 10-13 M, replicated the extracts of larval washings in biasing adults into a tributary stream. Our results reveal a pheromone that bridges two distinct life stages and guides orientation over a large space that spans two different habitats. The identified molecule may be useful for control of the sea lamprey.

Trace Amines and Their Receptors.

Trace amines are endogenous compounds classically regarded as comprising β-phenylethyalmine, p-tyramine, tryptamine, p-octopamine, and some of their metabolites. They are also abundant in common foodstuffs and can be produced and degraded by the constitutive microbiota. The ability to use trace amines has arisen at least twice during evolution, with distinct receptor families present in invertebrates and vertebrates. The term "trace amine" was coined to reflect the low tissue levels in mammals; however, invertebrates have relatively high levels where they function like mammalian adrenergic systems, involved in "fight-or-flight" responses. Vertebrates express a family of receptors termed trace amine-associated receptors (TAARs). Humans possess six functional isoforms (TAAR1, TAAR2, TAAR5, TAAR6, TAAR8, and TAAR9), whereas some fish species express over 100. With the exception of TAAR1, TAARs are expressed in olfactory epithelium neurons, where they detect diverse ethological signals including predators, spoiled food, migratory cues, and pheromones. Outside the olfactory system, TAAR1 is the most thoroughly studied and has both central and peripheral roles. In the brain, TAAR1 acts as a rheostat of dopaminergic, glutamatergic, and serotonergic neurotransmission and has been identified as a novel therapeutic target for schizophrenia, depression, and addiction. In the periphery, TAAR1 regulates nutrient-induced hormone secretion, suggesting its potential as a novel therapeutic target for diabetes and obesity. TAAR1 may also regulate immune responses by regulating leukocyte differentiation and activation. This article provides a comprehensive review of the current state of knowledge of the evolution, physiologic functions, pharmacology, molecular mechanisms, and therapeutic potential of trace amines and their receptors in vertebrates and invertebrates.

The influence of environmental cues on the activity of silver eels (Anguilla dieffenbachii) in Lake Manapouri, New Zealand

ABSTRACTLake Manapouri in the South Island of New Zealand has a significant hydroelectric generation facility, which potentially has a negative impact on the successful emigration of longfin eels (Anguilla dieffenbachii) from the upper Waiau catchment. Consequently, a trap-and-transfer programme has been implemented to allow silver (migratory) eels access to the sea. The present study analysed data on the timing of captures and numbers of silver eels over four seasons, including the influence of possible migration cues. Silver eels were captured over an extended season of seven months (November–May), with peak numbers during December and January. Flow at the lake outflow was found to have a weak relationship with the number of eels caught, as did lake level, but moon phase and rainfall had no significant effect. These results highlight the variability in silver longfin eel behaviour both in terms of timing and response to potential environmental cues.

Redirecting adult mesenchymal stromal cells to the brain: a new approach for treating CNS autoimmunity and neuroinflammation?

Mesenchymal stromal cells or stem cells (MSCs) have been shown to participate in tissue repair and are immunomodulatory in neuropathological settings. Given this, their potential use in developing a new generation of personalized therapies for autoimmune and inflammatory diseases of the central nervous system (CNS) will be explored. To effectively exert these effector functions, MSCs must first gain entry into damaged neural tissues, a process that has been demonstrated to be a limiting factor in their therapeutic efficacy. In this review, we discuss approaches to maximize the therapeutic efficacy of MSCs by altering their intrinsic trafficking programs to effectively enter neuropathological sites. To this end, we explore the significant role of chemokine receptors and adhesion molecules in directing cellular traffic to the inflamed CNS and the capacity of MSCs to adopt these molecular mechanisms to gain entry to this site. We postulate that understanding and exploiting these migratory mechanisms may be key to the development of cell-based therapies tailored to respond to the migratory cues unique to the nature and stage of progression of individual CNS disorders.

Decreased stock entering the Belgian Meuse is associated with the loss of colonisation behaviour in yellow-phase European eels

The upstream migratory behaviour of yellow-phase European eels was investigated in regulated inland rivers (>320 km upstream the sea), where the stock is in drastic decline. From 2010 to 2015, eels entering the Belgian Meuse River (n = 1357; total length, 231–755 mm) were caught in fish passes, tagged with a pit-tag and released. Their upstream movements were tracked during the next six consecutive years, using three detection stations installed in vertical-slot fish passes of the Meuse and its Ourthe tributary. Among the 1357 eels tagged, 27.6% (n = 374 individuals) were detected at one or more of the three upstream detection stations. Only 6.6% (n = 89) of tagged eels were detected at the two subsequent stations. In this last group, most of the detected eels continued to move upstream through the Meuse rather than leaving it for the Ourthe. Water temperature >13 °C, river flow 24–226 m3/s, dark time 00:00–05:00 h and the spring–summer seasons were the most important cues for upstream migration. Temperatures and flows at detection did not differ between size classes of ascending eels, while the detection period was earlier and daily speed was faster in large (>450 mm) eels. However, small (≤300 mm) eels moved further upstream at slow speeds because they alternated between short periods of movement and long stationary periods. This behaviour suggests the existence of a few nomad individuals and probably more home range dwellers in the entering population. Small eels were better suited to colonise upper rivers.

A compound scaffold with uniform longitudinally oriented guidance cues and a porous sheath promotes peripheral nerve regeneration in vivo.

Scaffolds with inner fillers displaying directional guidance cues represent a promising candidate for nerve repair. However, further clinical translation should pay attention to the problem of non-uniform distribution of inner fillers, the porosity and mechanical properties of the outer sheath and the morphological design facilitating operation. In this study, a stage-wise fabrication strategy was used, which made it possible to develop an O-CCH/PCL compound scaffold with a uniform longitudinally oriented inner filler and a porous outer sheath. The uniform distribution of the pores in the O-CCH/PCL scaffold provides a solution to resolve the problem of non-uniform distribution of inner fillers, which impede the clinical translation of scaffolds with longitudinal microstructured fillers, especially for aligned-fiber-based scaffolds. In vitro and in vivo studies indicated that the O-CCH/PCL scaffolds could provide topographical cues for axonal regeneration and SC migration, which were not found for random scaffolds (with random microstructure resemble sponge-based scaffolds). The electrospun porous PCL sheath of the O-CCH/PCL scaffold not only prevented fibroblast infiltration, but also satisfied the mechanical requirements for clinical use, paving the way for clinical translation. The differential degradation time of the O-CCH filler and the PCL sheath makes O-CCH/PCL scaffold able to provide long protection for regenerating axons from compression stress, but enough space for regenerating nerve. These findings highlight the possibility of developing an optimal therapeutic alternative for nerve defects using the O-CCH/PCL scaffold.

The opposing forces of shear flow and sphingosine-1-phosphate control marginal zone B cell shuttling

Splenic marginal zone B cells (MZB) shuttle between the blood-filled marginal zone for antigen collection and the follicle for antigen delivery. However, it is unclear how MZBs migrate directionally from the marginal zone to the follicle. Here, we show that murine MZBs migrate up shear flow via the LFA-1 (αLβ2) integrin ligand ICAM-1, but adhere or migrate down the flow via the VLA-4 integrin (α4β1) ligand VCAM-1. MZBs lacking Arhgef6 (Pak-interacting exchange factor (αPIX)) or functional LFA-1 are impaired in shuttling due to mislocalization toward the VCAM-1-rich red pulp. Sphingosine-1-phosphate (S1P) signaling through the S1PR3 receptor inhibits MZB migration up the flow, and deletion of S1pr3 in Arhgef6−/− mice rescues mislocalized MZBs. These findings establish shear flow as a directional cue for MZB migration to the follicle, and define S1PR3 and VCAM-1 as counteracting forces that inhibit this migration.

Endothelial cell-derived GABA signaling modulates neuronal migration and postnatal behavior

The cerebral cortex is essential for integration and processing of information that is required for most behaviors. The exquisitely precise laminar organization of the cerebral cortex arises during embryonic development when neurons migrate successively from ventricular zones to coalesce into specific cortical layers. While radial glia act as guide rails for projection neuron migration, pre-formed vascular networks provide support and guidance cues for GABAergic interneuron migration. This study provides novel conceptual and mechanistic insights into this paradigm of vascular-neuronal interactions, revealing new mechanisms of GABA and its receptor-mediated signaling via embryonic forebrain endothelial cells. With the use of two new endothelial cell specific conditional mouse models of the GABA pathway (Gabrb3ΔTie2-Cre and VgatΔTie2-Cre), we show that partial or complete loss of GABA release from endothelial cells during embryogenesis results in vascular defects and impairs long-distance migration and positioning of cortical interneurons. The downstream effects of perturbed endothelial cell-derived GABA signaling are critical, leading to lasting changes to cortical circuits and persistent behavioral deficits. Furthermore, we illustrate new mechanisms of activation of GABA signaling in forebrain endothelial cells that promotes their migration, angiogenesis and acquisition of blood-brain barrier properties. Our findings uncover and elucidate a novel endothelial GABA signaling pathway in the CNS that is distinct from the classical neuronal GABA signaling pathway and shed new light on the etiology and pathophysiology of neuropsychiatric diseases, such as autism spectrum disorders, epilepsy, anxiety, depression and schizophrenia.

Impacts of fishing, river flow and connectivity loss on the conservation of a migratory fish population

Abstract Migratory species depend on connected habitats and appropriate migratory cues to complete their life cycles. Diadromous fish exemplify species with migratory life cycles by moving between connected freshwater and saltwater habitats to reproduce. However, migration increases the exposure of fish to multiple threats and it is critical that managers integrate habitat connectivity into resource management and conservation. The benefit of alternative management actions was assessed for a diadromous fish, the Australian bass Percalates novemaculeata, using a spatio‐temporal population model informed by individual‐based movement data. The management actions comprise seasonal closures during the spawning season, and controlling fishing pressure by limiting catch or effort. The benefits of implementing seasonal closures depend upon interactions among how fishing pressure is controlled, the response of anglers to fishery regulations and river flow regimes. The results indicated that seasonal closures are ineffective if fishing pressure is merely displaced to another location or time of year. In addition, shifting seasonal closures from spawning grounds to feeding grounds increased population abundances under low flow events when fishing effort was also controlled. However, when total annual catch is limited by a fishery closure, changing the location of seasonal closure schemes had little effect. The findings in this study highlight the need for flexible management strategies that account for migratory movements and respond both to variations in connectivity (e.g. river flow regime) and direct pressures on survivorship (e.g. exploitation). As the implementation of one management action (e.g. fishing or water regulation) could affect the influence of another management action, this study emphasizes the importance of cooperation between resource managers in conserving migratory species.

A pilgrim's progress: Seeking meaning in primordial germ cell migration

Comparative studies of primordial germ cell (PGC) development across organisms in many phyla reveal surprising diversity in the route of migration, timing and underlying molecular mechanisms, suggesting that the process of migration itself is conserved. However, beyond the perfunctory transport of cellular precursors to their later arising home of the gonads, does PGC migration serve a function? Here we propose that the process of migration plays an additional role in quality control, by eliminating PGCs incapable of completing migration as well as through mechanisms that favor PGCs capable of responding appropriately to migration cues. Focusing on PGCs in mice, we explore evidence for a selective capacity of migration, considering the tandem regulation of proliferation and migration, cell-intrinsic and extrinsic control, the potential for tumors derived from failed PGC migrants, the potential mechanisms by which migratory PGCs vary in their cellular behaviors, and corresponding effects on development. We discuss the implications of a selective role of PGC migration for in vitro gametogenesis.

Migration Trends of Sockeye Salmon at the Northern Edge of Their Distribution

AbstractClimate change is affecting arctic and subarctic ecosystems, and anadromous fish such as Pacific salmon Oncorhynchus spp. are particularly susceptible due to the physiological challenge of spawning migrations. Predicting how migratory timing will change under Arctic warming scenarios requires an understanding of how environmental factors drive salmon migrations. Multiple mechanisms exist by which environmental conditions may influence migrating salmon, including altered migration cues from the ocean and natal river. We explored relationships between interannual variability and annual migration timing (2003–2014) of Sockeye Salmon O. nerka in a subarctic watershed with environmental conditions at broad, intermediate, and local spatial scales. Low numbers of Sockeye Salmon have returned to this high‐latitude watershed in recent years, and run size has been a dominant influence on the migration duration and the midpoint date of the run. The duration of the migration upriver varied by as much as 25 d across years, and shorter run durations were associated with smaller run sizes. The duration of the migration was also extended with warmer sea surface temperatures in the staging area and lower values of the North Pacific Index. The midpoint date of the total run was earlier when the run size was larger, whereas the midpoint date was delayed during years in which river temperatures warmed earlier in the season. Documenting factors related to the migration of Sockeye Salmon near the northern limit of their range provides insights into the determinants of salmon migrations and suggests processes that could be important for determining future changes in arctic and subarctic ecosystems.Received October 24, 2016; accepted March 2, 2017 Published online June 8, 2017

IL-17-producing \u03b3\u03b4 T cells switch migratory patterns between resting and activated states

Interleukin 17-producing γδ T (γδT17) cells have unconventional trafficking characteristics, residing in mucocutaneous tissues but also homing into inflamed tissues via circulation. Despite being fundamental to γδT17-driven early protective immunity and exacerbation of autoimmunity and cancer, migratory cues controlling γδT17 cell positioning in barrier tissues and recruitment to inflammatory sites are still unclear. Here we show that γδT17 cells constitutively express chemokine receptors CCR6 and CCR2. While CCR6 recruits resting γδT17 cells to the dermis, CCR2 drives rapid γδT17 cell recruitment to inflamed tissues during autoimmunity, cancer and infection. Downregulation of CCR6 by IRF4 and BATF upon γδT17 activation is required for optimal recruitment of γδT17 cells to inflamed tissue by preventing their sequestration into uninflamed dermis. These findings establish a lymphocyte trafficking model whereby a hierarchy of homing signals is prioritized by dynamic receptor expression to drive both tissue surveillance and rapid recruitment of γδT17 cells to inflammatory lesions.

22016 ATVB Plenary Lecture: Receptor for Advanced Glycation Endproducts and Implications for the Pathogenesis and Treatment of Cardiometabolic Disorders: Spotlight on the Macrophage.

The receptor for advanced glycation endproducts (RAGE) interacts with a unique repertoire of ligands that form and collect in the tissues and circulation in diabetes mellitus, aging, inflammation, renal failure, and obesity. RAGE is expressed on multiple cell types linked to tissue perturbation in these settings. This brief review focuses on the role of RAGE in monocytes/macrophages and how RAGE ligand engagement on these cells mediates seminal changes in monocyte/macrophage migration, oxidative stress, cholesterol efflux, and pro- versus anti-inflammatory cues that signal to tissue damage. Studies using mice devoid of Ager (gene encoding RAGE) or pharmacological antagonists of RAGE are protective in animal models of diabetes mellitus, atherosclerosis, and high-fat diet-induced obesity, in least in part through key roles in monocytes/macrophages. RAGE signal transduction requires the interaction of RAGE cytoplasmic domain with the formin, DIAPH1 (diaphanous 1) and novel antagonists of this interaction show significant promise in attenuation of the maladaptive effects of RAGE ligands in cellular and in vivo models. Finally, this brief review discusses evidence for RAGE axis perturbation in human monocytes/macrophages and how tracing RAGE activity in these cells may identify target engagement biomarkers of RAGE antagonism for future clinical trials.

EphA4 Regulates Neuroblast and Astrocyte Organization in a Neurogenic Niche.

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.SIGNIFICANCE STATEMENT The subventricular zone neurogenic stem cell niche generates highly migratory neuroblasts that transit the anterior forebrain along a defined pathway to the olfactory bulb. Postnatal and adult brain organization dictates strict adherence to a narrow migration corridor. Subventricular zone neuroblasts are aligned in tightly bundled chains within a meshwork of astrocytes; however, the cell-cell cues that organize this unique, cell-dense migration pathway are largely unknown. Our studies show that forward signaling through the EphA4 tyrosine kinase receptor, mediated by ephrins expressed by subpopulations of neuroblasts and astrocytes, is required for compact, directional organization of neuroblasts and astrocytes within the pathway and efficient transit of neuroblasts through the anterior forebrain to the olfactory bulb.