Trends in Neurosciences
Is there a neural stem cell in the mammalian forebrain?
Section snippets
in vitro studies of the developing CNS provided the first evidence for multipotent precursors
The adult mammalian CNS contains a variety of cell types that arise over a short period of time from a small number of cells in the neural tube. While thymidine-labeling studies have described the temporal generation of the diverse neural cell types during this developmental program, little is known about the specific molecular signals that initiate and terminate this process. Neurons and glia are generated primarily during different developmental periods (neurons prenatally and glia postnatally
in vivo lineage studies reveal limited proliferative and phenotype potential of neural precursors
Despite the in vitro results cited in the previous section, most in vivo attempts to study precursor cells during embryonic mammalian brain development have not revealed multipotential neural cells. Retroviral lineage tracing, where limiting dilutions of a retrovirally carried marker gene are injected into the ventricular system of relatively early (primarily embryonic) rat and mouse brains to label one or a few germinal-zone cells, reveals that most of the clones contain either only neuronal
EGF induces the in vitro proliferation of multipotential cells
Recently, we37 and others12,38 reported the isolation, in vitro, of precursors responsive to epidermal growth factor (EGF) and transforming growth factor-α (TGF-α) that generated neurons and glia from late embryonic forebrain and retina, respectively. The forebrain precursor37 gave rise to spheres of relatively undifferentiated cells, defined by the absence of antigens characteristic of mature nerve cells and the presence of nestin, a neuroectodermal cell marker. These spheres of cells, whose
The embryonic EGF-responsive precursor is a stem cell that self-renews and produces progenitor cells
Given the functional definitions of stem cells outlined above, and the lack of previous identification of CNS cells that meet those criteria, we asked whether the EGF-responsive precursor was indeed a true stem cell. Thus, we undertook a rigorous clonal and population analysis of the in vitro properties of the EGFresponsive embryonic precursor and found that the cell indeed exhibits properties described previously only for stem cells of non-neural origin40. The focus of the study was
Sequential growth-factor actions might regulate restriction of EGF-responsive, stem cell-generated precursors to the neuronal lineage
As detailed above for hematopoiesis, a common feature of stem cells is the generation of proliferating progenitor cells that generate the differentiated cells of the tissue. It is by successive restriction that fully differentiated postmitotic cells are generated. After finding that the relatively undifferentiated cells within the EGF-responsive spheres generated by stem cells expressed FGFR1 (the bFGF receptor), we examined the actions of bFGF on single cells dissociated from these spheres.
Is there evidence for cell turnover in the adult forebrain in vivo that would require the presence of a stem cell?
In one sense, neural stem cells in vivo can only be defined in the adult organism. This is because of the two primary criteria for defining stem cells (self-renewal and multipotentiality), self-renewal can be assessed effectively only over the longer time periods available in vivo in the adult. Certainly new neurons and glia are generated throughout adulthood in the avian brain44,45, although there is no in vivo evidence in birds for multipotentiality (that neurons and glia arise clonally from
An adult stem cell, with identity to the in vitro sphere-producing cell, resides in the subependyma
The embryonic germinal zone of the forebrain shrinks postnatally to form the subependymal lining of the lateral ventricles (the subependymal zone), which in the adult borders the striatum, septum and corpus callosum (Fig. 3). The subependyma of the mammalian forebrain lateral ventricle contains the largest population of rapidly and constitutively proliferating population of cells in the adult brain55,56. No other part of the adult ventricular system contains a subependyma with constitutively
Infusion of EGF into the lateral ventricle results in the modulation of subependymal neural stem and progenitor cells in vivo
Given that EGF generates spheres from single neural stem cells in vitro, it was hypothesized that EGF might also expand the subependymal population in vivo. Continuous infusion of EGF into the adult murine lateral ventricle for six days increases the population of retrovirally labeled subependymal cells by 17-fold compared to saline infusion63. This expansion can be attributed to the induction of symmetric divisions of the relatively quiescent stem cell, to increasing the proliferation of both
A counter-intuitive thought, unanswered questions and prospects for the future
Retroviral lineage tracing of germinal-zone cells in the mammalian embryo suggests that restricted progenitor cell populations greatly outnumber the relatively few multipotential and self-renewing neural stem cells. However, the dramatic shrinkage of the constitutively proliferating progenitor cell population in the adult forebrain subependyma might produce a relative (although probably not absolute) enrichment of neural stem cells. Coupled with the apparent role these cells play in replacement
Acknowledgements
Support for the studies, reviewed in this manuscript, to the Weiss and van der Kooy laboratories was from the Medical Research Council of Canada (MRC), the Alberta Heritage Foundation for Medical Research (AHFMR), Ciba-Geigy Canada Ltd, and the NeuroScience Network of the National Centres of Excellence (NCE). Support to ALV was from the Italian Ministry of Health. CM is recipient of an MRC Fellowship, CGC is an MRC and NCE Fellow, SW is an AHFMR Scholar and MRC Scientist, and DvdK is an MRC
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