Identification of neural stem cells in the adult vertebrate brain

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Abstract

Neurogenesis continues into adult life in restricted germinal layers. The identification of the neural stem cells that give rise to these new neurons has important clinical implications and provides fundamental information to understand the origins of the new neurons. Work in adult birds and rodents yielded a surprising result: the neural stem cells appear to have characteristics of glia. In adult birds, the primary neuronal precursors are radial glia. In adult mammals, the primary neuronal precursors have properties of astrocytes. Radial glial cells have previously been shown to transform into astrocytes; both cell types are classically considered part of a committed astroglial lineage. Instead, we propose that neural stem cells are contained within this astroglial lineage. These findings in adult vertebrate brain, together with recent work in the developing mammalian cerebral cortex, force us to reexamine traditional concepts about the origin of neurons and glia in the central nervous system. In particular, neural stem cells possess a surprisingly elaborate structure, suggesting that in addition to their progenitor role, they have important structural and metabolic support functions. The very same cells that give birth to new neurons also seem to nurture their maturation and support their function.

Introduction

The adult brain retains neural stem cells. Two lines of investigation support this notion: (1) Primary precursors within central nervous system (CNS) germinal zones continue to produce neurons and glia throughout an animal’s life, and (2) cells from the adult brain with properties of neural stem cells can be grown in vitro with growth factors. In this review we will focus on the in vivo identification of the primary precursors for new neurons in the adult brain. Several reviews have dealt with the properties of neural stem cells grown in vitro 26, 65, 97, 101.

For adult neurogenesis to occur, primary precursors, or stem cells, need to be retained within the germinal zones 10, 30. Evidently, a critical step towards understanding adult neurogenesis is the identification of the primary precursors that generate the new neurons in vivo and stem cells in vitro. The identification of the stem cells is also critically important for future attempts to engineer these cells for therapeutic applications. This requires understanding of the cell types and organization of the germinal zones where the new neurons are born.

Here we will discuss work in adult mammals and birds that indicate how germinal zones are organized in the adult and which cells within these germinal regions correspond to the stem cells. We have recently discussed how information on the identity of neural stem cells in the adult may be integrated with emerging work in the developing mammalian brain to provide a unified concept about the development of neural stem cells 7, 55. In the present review we further extend this hypothesis with the proposition that radial glia and astrocytes share not only the germinal capacity, but also the structural and biochemical support functions of the early neuroepithelium.

Section snippets

A ventricular zone persists in adult birds: radial glia as neuronal progenitors

In adult canaries new neurons are incorporated throughout most of the telencephalon, but not outside of it 10, 30, 74, 80. This spatial restriction emerges during development around hatching [9]. Neurons are born in the walls of the lateral ventricle 13, 30 from which they migrate long distances to reach most areas of the telencephalon [10]. Old neurons are continuously replaced with new ones 45, 75 in a process thought to be related to plasticity and learning 8, 74.

The proliferative layer in

Germinal zones in the adult mammalian brain: astrocytes as stem cells

Neurogenesis also continues in restricted regions of the adult mammalian CNS. Neuronal birth in adult mammals has been demonstrated in two brain regions: (1) in the subventricular zone (SVZ) of the lateral ventricle 57, 58, and (2) in the subgranular layer (SGL) of the hippocampal dentate gyrus 15, 28, 42. In the adult mammalian brain, very few, if any, radial glial cells are retained into adult life, raising the question of the identity of the primary precursors for these new neurons.

Radial glia and astrocytes: origin and support of nerve cells

The identification of astrocytes and radial glia as progenitors that give rise to neurons is surprising, based on the classical concept that these cells are part of the astroglial lineage. The SVZ and SGL germinal cells in the adult brain have many characteristics of astrocytes, including elaborate processes that contain GFAP 21, 23, 82, 87. GFAP has been extensively used as a marker of terminally differentiated astrocytes. Clearly, the cells that are functioning as stem cells in the SGL and

Acknowledgements

Supported in part by National Institutes of Health grants NS28478, HD32116 and the Sandler Family Supporting Foundation to A.A-B.

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