Neural stem cells and regulation of cell number

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Abstract

Normal CNS development involves the sequential differentiation of multipotent stem cells. Alteration of the numbers of stem cells, their self-renewal ability, or their proliferative capacity will have major effects on the appropriate development of the nervous system. In this review, we discuss different mechanisms that regulate neural stem cell differentiation. Proliferation signals and cell cycle regulators may regulate cell kinetics or total number of cell divisions. Loss of trophic support and cytokine receptor activation may differentially contribute to the induction of cell death at specific stages of development. Signaling from differentiated progeny or asymmetric distribution of specific molecules may alter the self-renewal characteristics of stem cells. We conclude that the final decision of a cell to self-renew, differentiate or remain quiescent is dependent on an integration of multiple signaling pathways and at each instant will depend on cell density, metabolic state, ligand availability, type and levels of receptor expression, and downstream cross-talk between distinct signaling pathways.

Section snippets

Regulation of stem cell numbers

The early-formed neural tube consists of proliferating, morphologically homogeneous cells termed neuroepithelial (NEP) stem cells (Kalyani et al., 1997). NEP cells or neural stem cells (NSCs) are initially present in a single layer of pseudostratified epithelium spanning the entire distance from the central canal to the external limiting membrane (Sauer and Chittenden, 1959, Sauer and Walker, 1959). As development proceeds, NSCs are restricted to the proliferating ventricular zone where they

Regulation of proliferation

Small changes in cell cycle kinetics can change the total number of cells generated significantly. Based on the total period of neurogenesis and the number of divisions of precursors during this period (based on cell cycle time) it has been estimated that a stem cell undergoes a total of 10–12 divisions (Takahashi et al., 1994). Increasing or decreasing the number of precursor cell divisions by even one will double or halve neuronal number, a significant change but a level of variation not

Proliferation signals

Several different pathways that interact to regulate cell division have been identified. Perhaps the best understood are those triggered by growth factors. Different growth factors act at different stages of stem cell development and differential growth of stem cells may serve to sculpt the developing brain. All stem cells and precursor cells respond to multiple growth factors, but the exact subset of growth factors acting at a specific stage may be unique for a particular stage of stem cell

Cell death

Regulation of neuronal cell number and connectivity by programmed cell death (PCD) is a well established and important aspect of normal development at later embryonic stages (reviewed in Deshmukh and Johnson, 1997). At earlier stages of brain development, region-specific cell death has been implicated in morphogenetic processes such as the closure of the hindbrain neural tube and the segment-specific elimination of rhombencephalic neural crest (reviewed in Graham et al., 1996, Kuan et al., 2000

Regulation of programmed cell death

The occurrence of PCD in the proliferative neuroepithelium raises the question of how the balance between maintenance and depletion of the progenitor pool size is appropriately controlled by the extracellular environment. In postmitotic neurons, cell survival and death are regulated by competition for extrinsically supplied neurotrophic growth factors (reviewed in Deshmukh and Johnson, 1997). Withdrawal of these growth factors induces cell death, but the stimuli that initiate these events in

Differentiation signals

The neuronogenetic interval in mouse spans 6 days (Takahashi et al., 1994). In the course of these 6 days the founder population and its progeny execute 11 cell cycles. With each successive cycle there is an increase in the fraction of postmitotic cells that leaves the cycle (the Q fraction) and also an increase in the length of the cell cycle due to an increase in the length of the G1 phase of the cycle (Cai et al., 1997a, Miyama et al., 1997). Gliogenesis commences a little bit later and

Asymmetric versus symmetric divisions

Multipotent cells in the VZ undergo both symmetrical and asymmetrical divisions. Cai et al. (1997b) used retroviral labeling to show that approximately 48% of labeled cells formed clusters located entirely within the VZ suggesting self-renewal via symmetrical divisions. Approximately 20% of cells, however, appeared to generate cells in both the VZ as well as in the mantle suggesting at least some asymmetrical divisions. Symmetrical divisions that generate two stem-like daughter cells will

Signal integration by stem cells

We have discussed how proliferative, apoptotic, and differentiation signals can act to regulate stem cell number and have shown how each specific set of signals can act at specific stages to regulate stem cell behavior. It is important to emphasize, however, that the particular decision a stem cell makes, be it to remain quiescent, proliferate, differentiate or die, represents the combinatorial action of multiple environmental signals. The sum total of these signals is assumed to constitute the

Acknowledgements

This work was supported by NIA, NINDS, NIDA, MDA, and the Swiss National Science Foundation. We thank all members of our laboratorie for their generous help with generating figures and critiquing the manuscript. We acknowledge YuanYuan Wu, Hye-Youn Lee and Rainer Leimeroth for their help with the figures. We thank Dr. Gary Schoenwolf, Dr. S. Temple and Dr. S. Goldman for their advice. MSR gratefully acknowledges the support of Dr. S. Rao through all phases of this project.

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