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    What molecular mechanisms are thought to control cell fate, particularly the differentiation of neuronal precursor cells into either neurons or glia?

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    1. What molecular mechanisms are thought to control cell fate, particularly the differentiation of neuronal precursor cells into either neurons or glia?

    Cell fate is determined by intrinsic programs and external cues, such as soluble signals and cell-cell contact. Previous studies have demonstrated the roles of soluble factors in the proliferation and differentiation of cortical stem cells and cell-cell contact in maintaining stem cells in a proliferative state. In the present study, we focused on the effect of cell-cell interaction on cell-fate determination. We found that density could exert a strong influence on the cell-type composition when cortical stem cells differentiate. Multipotent stem cells, which normally gave rise to neurons, astrocytes, and oligodendrocytes under high-density culture condition, differentiated almost exclusively into smooth muscle at low density. Clonal analysis indicated that smooth muscle and astrocytes were derived from a common precursor and that the density effect on cell types used an instructive mechanism on the choice of fate rather than an effect of selective survival and/or proliferation. This instructive mechanism depended on the local and not the average density of the cells. This local signal could be mimicked by membrane extract. These findings demonstrate the importance of membrane-bound signals in specifying lineage and provide the first evidence for a short-range regulatory mechanism in cortical stem cell differentiation. (See full article http://www.jneurosci.org/cgi/content/full/20/10/3725).

    The nervous system contains an incredible variety of cell types. The structural and molecular differences seen are of critical importance to the function of nerve cells in nervous system circuits. The establishment of cellular identity (cell fate determination) is a step-wise differentiation process of neuronal precursor cells into either neurons or glia that involves a progressive restriction of potential. Certainly there are not enough genes in the genome to specify the fates of the 100 billion nerve cells in the human brain!

    Many intrinsic and extrinsic factors are involved in the differentiation process:
    • Sources of information for fate determination
    o Intrinsic ("European Plan")
    • molecules inherited from precursors
    • lineage relations
    o Extrinsic Induction ("American Plan")
    • Surrounding cells
    • Surface molecules
    • Diffusible molecules
    • Neurotransmitters
    • Electrical activity
    • Extracellular matrix (ECM)
    • External influences such as hormones, sensory experience
    • What characteristics differ between different neurons?
    o Location
    o Size and shape (including axonal and dendritic morphology)
    o Chemistry (neurotransmitters, secreted substances, etc)
    o Connectivity (including synaptic strength)
    o Physiology (including channel types expressed)
    • Techniques for studying neuronal determination
    o Characterization of cell type through anatomical, neurochemical (ICC), molecular (ISH), or physiological techniques
    o Ablation of cell or its neighbors
    o Transplantation to challenge the role of time and location in determination
    • homo vs heterotopic
    • homo vs heterochronic
    o in vitro isolation and stepwise addition of signaling molecules
    o genetic manipulation

    • The current understanding includes the following general principles cell fate:
    o Fate is established in a stepwise, hierarchical manner by genetic "subprograms" that can be implemented in series or in parallel, rather than by one master program.
    o Some subprogram combinations are possible and some are not.
    o Some stem cells are partially restricted, but most cells are pluripotent during migration.
    o There are multiple mechanisms for establishing cell fate (see attached article)
    o Positional specification moleculrar mechanisms can be independent of cell-type specification (e.g. Hox genes control positional fate in rhombomeres but homeodomain genes can also, later or separately, specify a particular cell type such as retinal bipolar cells).
    o Lineage-dependent molecular mechanisms are somewhat more important in invertebrates and inductive mechanisms in vertebrates.
    o Master genes (panneuronal, panglial) are found in invertebrates; homologous genes found in vertebrates may have a similar function but are more restricted in spatial distribution (e.g. Pax6 in retina), perhaps tied to positional specification genes.
    o Lineage-dependent and -independent processes can interact.
    o Transcription factors play early roles in stepwise narrowing of potential fates.
    • The bHLH proneural genes establish neuronal fate.
    • Homeobox and paired domain transcription factors cause a further partial restriction of fate.
    • POU and LIM domain transcription factors cause further specification.
    o Signaling molecules/morphogens play a role, often later on, such as:
    • Delta/Notch
    • TGFß
    • Shh
    • RA
    • Control of cell fate in C. elegans through lineage-dependent cascades of transcription factors
    o An individual lineage can give rise to neuronal and non-neuronal cells.
    o Deletion of precursors eliminates neuronal and non-neuronal descendents (not replaced).
    o Induced mutations can be used to delineate the genetic pathways leading to determination of each cell's fate.
    • unc-86 sensory pathway
    • Mutational loss of the single gene unc-86 (POU homeodomain family) transforms the Q1.p precursor of mechanosensory and touch cells into a stem cell, preventing ...

    Solution Summary

    This solution fully discuses the molecular mechanisms that are thought to control cell fate, particularly the differentiation of neuronal precursor cells into either neurons or glia. References are provided along with an informative article on mechanisms of neuronal cell fate.