Postnatal neuronal migration in health and disease

https://doi.org/10.1016/j.conb.2020.06.001Get rights and content

Highlights

  • Neuroblast migration in the postnatal brain is controlled by extrinsic and intrinsic mechanisms.

  • Neuroblast migration toward a lesion is mediated by both physiological and pathologically induced mechanisms.

  • Manipulations of these mechanisms can promote neuroblast migration and regeneration of functional neurons.

Postnatal neuronal migration modulates neuronal circuit formation and function throughout life and is conserved among species. Pathological conditions activate the generation of neuroblasts in the ventricular-subventricular zone (V-SVZ) and promote their migration towards a lesion. However, the neuroblasts generally terminate their migration before reaching the lesion site unless their intrinsic capacity is modified or the environment is improved. It is important to understand which factors impede neuronal migration for functional recovery of the brain. We highlight similarities and differences in the mechanisms of neuroblast migration under physiological and pathological conditions to provide novel insights into endogenous neuronal regeneration.

Introduction

Neurogenesis and neuronal migration are fundamental processes in the organization and function of the central nervous system (CNS). During development, newly generated immature neurons (neuroblasts) migrate from germinal zones toward their final destinations. Efficient neuroblast migration is supported by surrounding scaffold cells, extracellular stimuli, intrinsic transcription and polarized morphology of the neuroblasts. The appropriate spatiotemporal positioning of neurons leads to neuronal circuit formation and, in turn, brain function. After initial neuronal circuits are established, extensive neuronal migration ceases but migration continues postnatally in specific niches to fine tune the network in response to external stimuli.

Since the first report of adult mammalian neurogenesis by Joseph Altman in the 1960s [1] the brain has been perceived as an organ with plasticity and regenerative capacity in various species. In mammals, neurogenesis in the V-SVZ of the lateral ventricles persists into the adult stage by retaining neural stem cells (NSCs) and producing neuroblasts [2]. These neuroblasts form chain-like homophilic associations and tangentially migrate through a meshwork of astrocytic glial tubes along the rostral migratory stream (RMS) toward the olfactory bulb (OB). Neuroblasts detach from the chains after reaching the OB core and migrate radially into the granule cell layer and glomerular layer, where they differentiate into mature olfactory interneurons and acquire functional properties [3, 4, 5]. The postnatal neurogenesis and neuroblast migration toward the OB is limited to a specific time window in primates but not in rodents [6]. Importantly, neurogenesis and neuroblast migration are enhanced by brain damage. Upon lesion, V-SVZ NSCs are activated [7] and produce neuroblast chains migrating toward injured sites [8, 9, 10]. The understanding of the mechanisms that underlie migration, final positioning, and circuit integration of neuroblasts after injury is still in its infancy. Here we focus on postnatal V-SVZ-derived neuroblast migration under physiological and pathological conditions and discuss the latest advances in the field. We further propose that elucidating the underlying mechanisms of endogenous neurogenesis will facilitate the generation of novel therapeutic approaches for neuronal regeneration and functional recovery.

Section snippets

Migratory mechanisms in normal postnatal brain

In the RMS, neuroblasts directly contact neighboring neuroblasts and astrocytes, and utilize these cells as their migratory scaffolds. Neuroblasts adhere to each other via adherent junction (AJ)-like structures during chain migration. Although the molecular components of AJ-like structures have not been identified, homophilic cell adhesion molecules, such as N-cadherin and PSA-NCAM, have been shown to regulate chain migration of neuroblasts [11,12]. Neuroblast-extracellular matrix (ECM)

Migratory mechanisms in injured postnatal brain

Brain injuries cause the loss of cells and trigger various changes in the affected tissue, which positively and negatively influence neuroblast migration. For example, while reactive astrocytes have neurotoxic effects and form glial scars [44], inflammation induces secretion of chemoattractants [24] and activation of quiescent NSCs [45], which eventually differentiate into neuroblasts [46].

Under such pathological conditions, V-SVZ-derived neuroblasts migrate toward lesions by using the

Biomaterials for promoting neuronal migration

For migration in injured areas, neuroblasts take advantage of endogenous scaffolds, such as blood vessels and radial glial fibers. However, these scaffolds are insufficient for continuous neuroblast migration and regeneration. The branched network morphology and low density of blood vessels are not optimal for efficient scaffolding of neuroblast migration. Radial glial fibers gradually decrease after birth and do not support neuroblast migration into the cortex in the late postnatal stage.

Conclusions

Neuroblast migration in physiological and pathological conditions share similarities, yet the extent of migration and appropriate targeting is hindered in the latter. The mammalian brain under pathological conditions is potentially more plastic than we had previously believed and the microenvironment can be remodeled to promote migrating neuroblasts. We need to better comprehend the contribution of cells and environmental factors in the injury site to the series of processes that underlie

Conflict of interest statement

Nothing declared.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We apologize to all whose work we could not cite because of space limitations. We are grateful to Naoko Kaneko, Mercedes Paredes, Armen Saghatelyan, and Diego García-González for their valuable comments on the manuscript, and Jeremy Allen (Edanz Group) for editing drafts of this manuscript. This work was supported by research grants from the Japan Agency for Medical Research and Development (AMED) (JP19bm0704033 [to K.S.], JP19gm1210007 [to K.S.], JP19jm0210060 [to M.S. and K.S.]), the Japan

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