"GENES ARE FOLLOWERS NOT LEADERS". Was Birds of feather...

From: CNCabej (cncabej_at_aol.com)
Date: 12/24/04

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    Date: Fri, 24 Dec 2004 22:56:54 +0000 (UTC)

    Having shown that expression of nonhousekeeping genes is regulated by signal
    cascades originating in the CNS, now let's see how it is possible for the CNS
    to manipulatively control the expression of those genes throughout the animal
    body, or how it generates that huge amount of information necessary for that
    regulation.

    MANIPULATIVE EXPRESSION OF GENES IN THE CENTRAL NERVOUS
            SYSTEM
      
    Owing to the pervasive presence of the nervous system throughout the animal
    body, the CNS is able to monitor the state of the living system down to the
    lowest cell level. In order to do this, a huge amount of data on the state of
    the structure and functions of the body have to be transmitted via afferents in
    the CNS. Initially these data are received by sensory neurons, which convert
    them into a "common currency", electrical signals in the form of spike trains
    and in this form they transmit these data in specific neural circuits in the
    CNS.

    In the neural circuit a the input of data is compared with the previous normal
    state; if a significant change is detected in the data of the specific circuit,
    the data are perceived as a stimulus, which is processed in the neural circuit.
    Both the conversion of (internal and external) stimuli in the neurons and their
    processing in neural circuits are computational, nongenetic processes.

    Usually the processing of various stimuli in specific neural circuits results
    in the release of a chemical from neurons of the circuit, which starts a signal
    cascade that ultimately leads to expression of a specific gene that normally
    is not expressed in extracerebral tissues, in response to that stimulus.
    Expression of these specific gene(s) is an adaptive event in the meaning that
    it tends to restore the impaired (changed) structure or function communicated
    by the stimulus.

    A basic feature of the expression of genes in the CNS is the fact that it
    depends not on the nature of stimulus but on the computational properties of
    the stimulus; expression of nonhousekeeping genes in the CNS, thus, is
    processing-dependent, not stimulus-dependent.

    Let's illustrate this with an example of an internal stimulus such as the
    change in the estradiol level. Estradiol is known to induce expression of a
    number of "estrogenic genes" such as cyclin D (1), igf-1, etc. But this is not
    what takes place in the brain (hypothalamus) where the drop/increase in the
    level of estradiol is perceived as a stimulus and processed in separate
    oestrogen-sensitive neural circuits, which release stimulating (dopamine and
    noradrenalin) /inhibiting (GABA and neuropeptide Y), thus inducing/suppressing
    synthesis of GnRH by hypothalamic GnRH genes, which as it is wellknown
    determines reproductive cycles and gametogenesis. Let's reiterate: the unique
    ability of the hypothalamus to produce GnRH in response to the drop of the
    level of estrogen is determined by processing in the neural circuits of the
    electrical STIMULUS (the change in the level of estrogen as perceived in the
    brain) not by the estrogen itself, for investigators say that "there is no
    concrete evidence for the direct regulation of GnRH neurons by oestradiol"
    (Smith and Jennes, 2001). The fact that processing of the electrical stimulus
    in the brain circuits makes possible for the CNS to obtain an adaptive result
    that is otherwise (by direct action of the estrogen) impossible stimulus shows
    that this processing-dependent mechanism of gene expression is manipulative.

    Here is an example of an external stimulus: In the Hawaiian cockroach,
    Diploptera punctata, chilling of the antennae has no effect on antennae
    themselves, but has one in an organ that is not affected by chilling; it causes
    suppression of mitotic divisions in the glands corpora allata. The mechanism of
    this action is clearly nongenetic. The data on the chilling of antennae is
    transmitted in the form of an electrical signal, perceived and processed in the
    insect's brain where neurons of pars intercerebralis send signals that suppress
    mitotic division in corpora allata. Severance of the ventral nerve cord prior
    to chilling prevents suppression of cell division in corpora allata.

    Both examples unambiguously show that it is not the direct effect of the
    stimulus on the cells (the stimulus does not affect directly the reacting cells
    and genes) but the chemical signals released by the neural circuits that
    process electrical signals, as representation of the stimulus, that determines
    expression of specific genes and physiological phenomena relate to them. Hence,
    the conclusion that expression of genes in the CNS is not stimulus-dependent
    but processing-dependent, i.e. computational, nongenetic and, hence epigenetic.

    In each of the presented examples, only one specific cell subtype out of more
    than 200 types of cells and only one gene out of ~20,000 genes of the genome is
    transcribed in response to the stimulus. The reason is evident: these
    particular cells are the only that receive the processing-generated
    information, in the form of neurotransmitters released by neurons of specific
    neural circuits.

    Numerous genes are already known to be expressed in this processing-dependent
    mode in the CNS: a group of up to 100 immediate early genes and 469 late
    response genes. In turn, they induce expression of many other genes that are
    not expressed in extraneural cells. Expression of genes in response to numerous
    proteins, which cannot reach the CNS because of the blood-brain barrier, is
    also determined by the processing of the input on fluctuations of their level
    in body fluids. By processing the circadian stimuli (day/night cycles), the
    hypothalamic SCN (suprachiasmatic stimuluis) regulates the circadian expression
    of thousands of genes that control the circadian physiology in metazoans.

    This ability of the CNS to generate information for starting signal cascades
    for activation/deactivation of genes is crucial during the individual
    development, after the phylotypic stage, when all the reserve of epigenetic
    information (maternal cytoplasmic factors) from the egg cell is exhausted. It
    has been demonstrated that the CNS is able to generate the information for
    specifying the majority of its trillions of highly specific connections during
    the embryonic life by processing the input of data in the form of spontaneous
    electrical activity. "The spontaneous electrical activity is responsible for
    sculpting circuits on the basis of the brain's "best guess"") Katz and Shatz,
    1996), i.e computationally, and that activity is thought to represent a
    "self-organizing property" of the CNS (Weliky, 1999). In the embryonic retina
    e.g., that activity "can produce highly stereotyped patterns of connections
    before the onset of visual experience" (Penn et al., 1998) and instruct
    formation of eye-specific layers (Shatz, 1996). By contrast, in absence of
    afferent input, normal neural circuits are not formed (Penn et al., 1998). Also
    experimental delay of muscle development (that is lack or insufficient input
    from the muscle) causes suspension of synaptic branching of respective
    motoneurons.

    Not only structural changes in the developing embryo are related to, and
    necessary for, the development of synaptic morphology and neural circuits. The
    reverse also is true, i.e., that the electrical activity of the CNS, and the
    synaptic morphology related to it, are necessary for the embryonic development
    . So, e.g. it is demonstrated that suppression of the spontaneous activity by
    paralyzing motoneurons in chick embryos, results in reduction of bone formation
    and muscle formation, whereas denervation totally prevents the development of
    muscles in duck embryos.

    The above experimental evidence may indicate that local innervation conveys
    information for developing muscles and bones in developing embryos.

    How does the CNS generate information for the individual development after the
    phylotypic stage? There is sufficient experimental evidence indicating that by
    processing internal stimuli from the embryonic developing structure embryonic
    neural circuits modify their structure and this modifies their chemical output
    leading to activation of other signal cascades and genes as well as the ensuing
    changes in morphology and physiology in consecutive stages of development.

    Next we are going to show the structure and functioning of the epigenetic
    system of heredity with the CNS at its core.

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