Neural stem cells and regulation of cell number
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.
References (201)
- et al.
Collagen type IV promotes the differentiation of neuronal progenitors and inhibits astroglial differentiation in cortical cell cultures
Brain Res. Dev. Brain Res.
(1998) Proliferation and migration of undifferentiated precursor cells in the rat during postnatal gliogenesis
Exp. Neurol.
(1966)- et al.
Regulation of vertebrate neural cell fate by transcription factors
Curr. Opin. Neurobiol.
(1996) - et al.
Telomere shortening and tumor formation by mouse cells lacking telomerase RNA (see comments)
Cell
(1997) Regeneration and proliferation of embryonic and adult rat hippocampal neurons in culture (see comments)
Exp. Neurol.
(1999)- et al.
Structural modification of fibroblast growth factor-binding heparan sulfate at a determinative stage of neural development
J. Biol. Chem.
(1998) - et al.
Extrinsic cues, intrinsic cues and microfilaments regulate asymmetric protein localization in Drosophila neuroblasts
Curr. Biol.
(1997) - et al.
Survival and process regrowth of purified chick retinal ganglion cells cultured in a growth factor lacking medium at low density. Modulation by extracellular matrix proteins
Brain Res. Dev. Brain Res.
(1999) - et al.
Neural precursor cells differentiating in the absence of Rb exhibit delayed terminal mitosis and deregulated E2F 1 and 3 activity
Dev. Biol.
(1999) - et al.
Apaf-1 (CED-4 homolog) regulates programmed cell death in mammalian development
Cell
(1998)
Cleavage orientation and the asymmetric inheritance of Notch-1 immunoreactivity in mammalian neurogenesis
Cell
Intrinsic polarity of mammalian neuroepithelial cells
Mol. Cell Neurosci.
Control of neurogenesis: lessons from frogs, fish and flies
Curr. Opin. Neurobiol.
Modulation of GAP-43 mRNA by GABA and glutamate in cultured cerebellar granule cells
Brain Res.
Cell death in early neural development: beyond the neurotrophic theory
Trends Neurosci.
Subventricular zone astrocytes are neural stem cells in the adult mammalian brain
Cell
Basic fibroblast growth factor upregulates steady-state levels of laminin B1 and B2 chain mRNA in cultured neuroepithelial cells
Exp. Cell Res.
p27Kip1 alters the response of cells to mitogen and is part of a cell intrinsic timer that arrests the cell cycle and initiates differentiation
Curr. Biol.
Diversification of cell cycle controls in developing embryos
Curr. Opin. Cell Biol.
Progression from extrinsic to intrinsic signaling in cell fate specification: a view from the nervous system
Cell
Environmental signals influence expression of a cortical areal phenotype in vitro independent of effects on progenitor cell proliferation
Dev. Biol.
Combinatorial signaling in the specification of unique cell fates
Cell
rax, Hes1, and Notch-1 promote the formation of Müller glia by postnatal retinal progenitor cells
Neuron
Radial glial identity is promoted by Notch-1 signaling in the murine forebrain
Neuron
Reply
Trends Neurosci.
Cell birth, cell death, cell diversity and DNA breaks: how do they all fit together?
Trends Neurosci.
Telomerase and mammalian ageing: a critical appraisal
Mech. Age. Dev.
Neural crest apoptosis and the establishment of craniofacial pattern: an honorable death
Mol. Cell Neurosci.
Community effects and related phenomena in development
Cell
Autonomic neurogenesis and apoptosis are alternative fates of progenitor cell communities induced by TGFbeta
Dev. Biol.
Differential requirement for caspase-9 in apoptotic pathways in vivo
Cell
Cooperative effect of antisense-Rb and antisense-p53 oligomers on the extension of life span in human diploid fibroblasts, TIG-1
Biochem. Biophys. Res. Commun.
Neuroepithelial stem cells from the embryonic spinal cord: isolation, characterization, and clonal analysis
Dev. Biol.
Mechanisms of asymmetric cell division during animal development
Curr. Opin. Cell Biol.
The Jnk1 and Jnk2 protein kinases are required for regional specific apoptosis during early brain development
Neuron
Mechanisms of programmed cell death in the developing brain
Trends Neurosci.
Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase-9
Cell
Clonal heterogeneity in the germinal zone of the developing rat telencephalon
Development
A unified hypothesis on the lineage of neural stem cells
Nat. Rev. Neurosci.
Can stem cells cross-lineage boundaries?
Nat. Med.
Activation of the GABA A receptor inhibits the proliferative effects of bFGF in cortical progenitor cells
Eur. J. Neurosci.
Notch signaling in the nervous system. Pieces still missing from the puzzle
Bioessays
The p75 neurotrophin receptor mediates neuronal apoptosis and is essential for naturally occurring sympathetic neuron death
J. Cell Biol.
HGF receptor associates with the antiapoptotic protein BAG-1 and prevents cell death
EMBO J.
The Notch-3 intracellular domain represses Notch-1-mediated activation through Hairy/Enhancer of split (HES) promoters
Development
Homeotic transformation of rhombomere identity after localized Hox-b1 misexpression
Science
Aspartate mutations in presenilin and gamma-secretase inhibitors both impair Notch-1 proteolysis and nuclear translocation with relative preservation of Notch-1 signaling
J. Neurochem.
Widespread programmed cell death in proliferative and postmitotic regions of the fetal cerebral cortex
Development
Programmed cell death is a universal feature of embryonic and postnatal neuroproliferative regions throughout the central nervous system
J. Comp. Neurol.
Structural comparison of fibroblast growth factor-specific heparan sulfates derived from a growing or differentiating neuroepithelial cell line
Glycobiology
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