Ontogeny of adult neural stem cells in the mammalian brain

Abstract

Neural stem cells (NSCs) persist into adulthood in the subgranular zone (SGZ) of the dentate gyrus in the hippocampus and in the ventricular-subventricular zone (V-SVZ) of the lateral ventricles, where they generate new neurons and glia cells that contribute to neural plasticity. A better understanding of the developmental process that enables NSCs to persist beyond development will provide insight into factors that determine the size and properties of the adult NSC pool and thus the capacity for life-long neurogenesis in the adult mammalian brain. We review current knowledge regarding the developmental origins of adult NSCs and the developmental process by which embryonic NSCs transition into their adult form. We also discuss potential mechanisms that might regulate proper establishment of the adult NSC pool, and propose future directions of research that will be key to unraveling how NSCs transform to establish the adult NSC pool in the mammalian brain.

Keywords: Dentate gyrus; Neural stem cells; Neurogenesis; Niche; Origin; Quiescence; Subgranular zone; Subventricular zone.

Fig. 1

Two models for the origin of adult neural stem cells in the subgranular zone and the ventricular-subventricular zone. (A) Radial glia (RG) in the embryonic dentate neuroepithelium (DNE) divide and begin to detach from the ventricle to enter the dentate migratory stream (DMS). Dentate gyrus (DG) neural stem cells (NSCs) from the DMS continuously arrive in the dentate primordium perinatally, where they divide and contribute to peak DG cytogenesis. During early postnatal development, DG NSCs transition to a quiescent state in the SGZ until reactivated in adulthood. At each developmental stage, DG NSCs give rise only to dentate granule neurons (DGNs) and astrocytes, but not CA1 or CA3 neurons, which originate from the ammonic neuroepithelium (ANE). CH, cortical hem. (B) RG in the embryonic ventricular zone generate cells for different regions of the brain depending on their location along the ventricle—RG in the medial pallium, dorsal pallium, and subpallium give rise to cells in the septum, cortex, and striatum, respectively. During mid-embryonic development, a subpopulation of RG transition to a quiescent state and remain quiescent until reactivated in adulthood. In adulthood, quiescent NSCs (B cells) give rise to different types of olfactory bulb interneurons and oligodendrocytes depending on their location along the ventricle, which corresponds to their embryonic origin—dorsal B cells give rise to superficial granule cells (GCs), tyrosine hydroxylase (TH)-expressing periglomerular cells (PGCs) and oligodendrocytes, medial B cells give rise to calretinin (CalR)-expressing GCs and PGCs, and ventral B cells give rise to calbindin (CaB)-expressing PGCs and deep GCs. Therefore, NSCs in the V-SVZ lineage undergo a fate switch between embryonic development and adulthood.

Fig. 2

Establishment of the adult neural stem cell pool and mature neurogenic niche in the dentate gyrus of the hippocampus. Embryonic dentate gyrus (DG) radial glia (RG) in the dentate neuroepithelium (DNE) divide to expand the RG population and generate intermediate progenitor cells, which serve as scaffolding for migrating RG that have. detached from the ventricle and entered the dentate migratory stream (DMS). The dentate primordium emerges during perinatal development, a time of peak cytogenesis and cell migration. NSCs continuously migrate into the dentate primordium from the DMS, peak neurogenesis occurs, astrocytes are generated, angiogenesis occurs, and microglia, oligodendrocyte precursor cells and immature interneurons migrate into the DG. The gross morphology of the DG begins to take shape during early postnatal development, as the DG NSCs transition to a quiescent state and transform into radial glia-like NSCs (RGLs). Cytogenesis declines and many cell types, including neurons and glia, begin a maturation process that extends across the first 3–4 postnatal weeks. The DG gains its adult form around P30 when most RGLs are quiescent and located in the SGZ, and other cell types have reached full maturation.

Fig. 3

Establishment of the adult neural stem cell pool and mature neurogenic niche in the ventricular-subventricular zone. Embryonic radial glia (RG) divide to expand the RG population and then to generate neurons. During mid-embryonic development, some RG divide to generate immature ependymal cells and quiescent RG. Infiltration of oligodendrocyte precursor cells and microglia and angiogenesis begin in the embryonic ventricular zone and continue throughout perinatal development. In addition, astrocyte generation and interneuron migration occur perinatally, as embryonically born neurons begin to mature. During early postnatal development, ependymal cells become multiciliated and become distinguishable from quiescent B cells, gliogenesis declines, and cellular maturation of many cell types continues. The V-SVZ gains its adult form around P30 when ependymal cells have expanded to their full size, niche cell types have completed their maturation and quiescent B cells can become reactivated to generate olfactory bulb interneurons. In addition to these stepwise changes, there are gradual changes in the composition of the cerebral spinal fluid and the accumulation of extracellular matrix over the course of development.