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

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

Date: Fri, 24 Dec 2004 22:56:51 +0000 (UTC)

Phil Roberts, Jr wrote:

CNCabej wrote:
>The hypothesis, in which form this theory was first presented, allowed to make
>the following predictions:
>1. Expression of nonhousekeeping genes in metazoans is controlled and >
regulated by signal cascades originating in the CNS.

P.R.:
Why the CNS as opposed to, say the adrenal glands, etc.?

N.C.:
The simplest answer would be that this was evolution's choice, but I know you
want to know whether I can, or I have, substantiated and validated the first
prediction of my theory. The answer to those question is simply :"Yes". What
follows is a compressed summary of facts proving that the function of
nonhousekeeping genes is under the ultimate control of the central nervous
system (CNS).
 
   THE NEURAL CONTROL OF EXPRESSION OF NONHOUSEKEEPING
         GENES IN METAZOANS

Genes in the genome of higher vertebrates can be grouped in two functionally
distinct groups:
- Housekeeping genes ( ~10,000 in an averaged estimation), which are necessary
for cell's subsistence, and
- Nonhousekeeping genes (~ 10,000-15,000) that carry out specific functions of
each type of cell, within the general scheme of the division of labor in
metazoans.
Given the fact that the proteins coded for by these genes are not related to
the needs of the cell itself, but to the demands of the organism, the
information for the spatial and temporal activation/inactivation of these genes
has to be of extracellular origin. Most of biologists would agree that this is
a function of extracellular signals, which via signal transduction pathways
regulate and control the function of nonhousekeeping genes.

What about the extracellular signals. They are molecules that need themselves
information about the time and place where they must be synthesized and
secreted. But how could we prove that, ultimately, information for
extracellular signals and activation/inactivation of specific nonhousekeeping
genes originates
in the CNS. By simply tracing back elements of the known signal cascades. This
would lead on to a generalized signal cascade similar to the following one.

1. The function of nonhousekeeping genes at the proximate level (the level at
which many genetic studies focus) is regulated by changes in chromatin
conformation caused by acetylation, deacetylation and methylation of histones.
Investigators have considered this proximate control to be an epigenetic
control of gene expression (Jenuwein and Allis, 2001; Arney et al., 2002; Reik
et al., 2001; Rideout et al., 2001; Nakayama et al., 2001).
2. There is extensive evidence that extracellular signals, such as steroid
hormones, retinoic acid (RA), thyroid hormones etc. by binding their nuclear
receptors form a ligand-receptor complex, which recruits a protein with
acetylase activity, which by loosing the chromatin structure makes
transcription of a specific gene possible.
3. Transcription factors, are regulatory proteins that regulate the function of
genes by binding to their regulatory regions, but to do so they first need: A.
to be activated by specific extracellular inducers, or B. to be activated by
being phosphorylated by terminal elements of signal transduction pathways. This
also is a proximate epigenetic control of gene expression.
3. Signal transduction pathways, which include a number of proteins that are
sequentially phosphorylated by extracellular signals ( protein hormones,
growth factors, secreted proteins, neuroactive substances, etc.) represent
probably the main route of the epigenetic control of gene expression.
4 Both protein hormones (including growth factors and neuropeptides) and
secreted signal proteins are but conveyors of upstream messages rather than
authentic messengers.
5. The synthesis of protein hormones secreted by terminal endocrine gland
(including the adrenal glands, mentioned by P.R.) and other cells is induced or
stimulated by respective specific hormones of the pituitary which, for this
reason, until a few decades ago, was considered to be the "master gland".
6. A great number of other inducers, growth factors, has been discovered during
these last decades. By binding to their specific receptors they also activate
signal transduction pathways and accordingly activate/inactivate specific
nonhousekeeping genes. They also are synthesized by hormones of the terminal
endocrine glands and other inducers. There is adequate experimental evidence
demonstrating that growth factors are mediators of the functions previously
atributed to hormones and their synthesis is regulated by hormones.
7. The secretion of the pituitary hormones also requires information and now we
know that all the pituitary hormones are secreted not by themselves but
according to signals (specific releasing hormones) secreted by the
hypothalamus, a part of the vertebrate brain.
8. Still upstream, all the hypothalamic neurohormones are secreted in response
to chemical signals from neural circuits of the nonhypothalamic brain (CNS).

This neural mechanism of control of expression of nonhousekeeping genes seems
to be a universal mechanism in metazoans. In anticipation of the
counterargument that we have not proven that this mechanism is operational in
all metazoans or for all nonhoussekeeping genes, I would argue that if such an
inductive argument were valid at all, it could be easily used against most of
the general concepts of modern biology. So, e.g. we are still far from knowing
all the species of animals on Earth, let alone to have investigated their DNA.
And still we have no doubt that, because of the common origin of life, the
genetic code and the known mechanisms of gene expression are valid for them as
are for the investigated metazoans. The common origin of metazoans and the
experimental evidence accumulated so far is more than adequate for infering
that the neural control of transcription of nonhousekeepin genes is the general
mode of their transcription in metazoans.

What is the nature of the information the CNS provides for activating signal
cascades leading to activation of specific nonhousekeeping genes. I'll try to
show that in another post tomorrow.

Thank you,

Nelson R. Cabej