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Thread: Signalling neuronal destiny (Nature)

  1. #1
    Senior Member KIM's Avatar
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    Signalling neuronal destiny (Nature)

    Ménard and colleagues report on a new signaling mechanism that allows growth factors to induce progenitor cells to commit to a neuronal lineage.

    During the development of the mammalian nervous system, progenitor cells seem to be driven by an intrinsic program to generate neurons and glia. But environmental cues also have an effect, as various growth factors and cytokines are involved in determining cell fate. For example, platelet-derived growth factor (PDGF) and neurotrophin-3 induce cortical progenitors to adopt a neuronal fate, whereas leukaemia inhibitory factor (LIF) and ciliary neurotrophic factor (CNTF) enhance glial differentiation. Until recently, little was known about the signalling mechanisms by which such factors mediate cortical neurogenesis and gliogenesis. So, LIF and CNTF have been shown to instruct glial differentiation by activating a receptor-associated tyrosine kinase, the Janus kinase (JaK), which in turn induces various signal transduction pathways and activators of transcription to activate glial-specific genes. Now, Ménard et al. report on a new signalling mechanism that allows growth factors to induce progenitor cells to commit to a neuronal lineage.


    CCAAT/enhancer-binding proteins (CEBPs) belong to the leucine-zipper family of transcription factors and are known regulators of differentiation in liver, fat tissue and blood. Ménard et al. asked whether CEBPs might also influence cell differentiation during brain development. They isolated progenitor cells from the cortex of mouse embryos, cultured them with various growth factors, including PDGF, and tested whether knocking down CEBP activity in these cells disrupted cortical neurogenesis. Using adenoviral vectors to infect progenitor cells with an inhibitory form of CEBP, the authors found that CEBPs are critical for neuronal differentiation. Cells that were made deficient in CEBP activity rarely gave rise to neurons and were unable to transcribe neuron-specific genes. Instead, blocking CEBP activity in cortical progenitor cells caused them to remain in an undifferentiated state. Importantly, adding CNTF to the cultures of progenitor cells shifted the phenotypic profile; most CEBP-deficient progenitors became glia in response to added CNTF. Ménard et al. used a similar approach and site-directed mutagenesis at a CEBP phosphorylation site to illustrate the importance of the mitogen-activated protein kinase kinase (MEK) for activating CEBPs.

    So, it seems that growth factors such as PDGF can instruct cortical progenitor cells along a neuronal lineage by activating a MEK, which in turn induces CEBPs to activate neuron-specific programs of gene expression and inhibit gliogenesis. Owing to this dual effect, the activation of the MEK-CEBP pathway might be a mechanism whereby growth factors can bias progenitors to become neurons during cortical development.

    Robin J. Lichtenwalner

    References
    Ménard, C. et al. An essential role for a MEK-C/EBP pathway during growth-factor-regulated cortical neurogenesis. Neuron 36, 597-610 (2002) | PubMed |
    Bonni, A. et al. Regulation of gliogenesis in the central nervous system by the JAK-STAT signaling pathway. Science 278, 477-483 (1997) | Article | PubMed |

  2. #2
    Senior Member Leo's Avatar
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    Thanks Kim,

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