THE EPIGENETIC SYSTEM OF HEREDITY
From: CNCabej (cncabej_at_aol.com)
Date: 01/13/05
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Date: Thu, 13 Jan 2005 06:13:38 +0000 (UTC)
THE EPIGENETIC SYSTEM OF HEREDITY
Part 2
THE EPIGENETIC CONTROL OF THE EARLY DEVELOPMENT
The control of the early development by cytoplasmic factors (=cerebrally
generated epigenetic information) maternally deposited in the egg cell is a
well established and generally acknowledged fact, already part of the general
developmental-biological education (Wolpert et al., 1998; Hall1998; Gilbert,
2000). Hence, logically it may be concluded that, by having demonstrated the
CNS control of the deposition of maternal cytoplasmic factors in the egg cell
and gene imprinting in egg- and sperm cells, we have also proven the control of
the early development by the maternal (in parthenogenetic organisms) or
parental CNS(s) (in dioecious animals). Therefore, we'll only focus on a few
important topics of the maternal control of the early development in three
groups of metazoans: insects, non-mammal vertebrates, and mammals.
Maternal Control of Early Development in Insects
Cleavage divisions that lead to formation of the syncytial blastoderm are
determined not by zygotic genes, but by cyclins and String proteins translated
from the respective maternally deposited mRNAs. The maternal source of these
transcripts is exhausted after the 17th division cycle. The maternal
neurotransmitter serotonin is also present in eggs of various insect species;
its presence "is necessary for correct development and morphogenesis." (Pennati
et al., 2001)
Early during the phylotypic stage, the incipient functioning CNS in insects is
involved in patterning the mesoderm and ectoderm, and in determining their cell
fates, especially formation of somatic muscles from mesodermal progenitors.
Maternal Control of Early Development in Nonmammalian Vertebrates
In vertebrates as well, cell divisions are induced by cyclins translated from
maternal cyclin mRNAs deposited in the egg cell. The reserve of cyclin and
String mRNAs is exhausted by the 14th cycle of cell division. The zygotic
string gene will be differentially expressed, i.e. in the cells that happen to
inherit MATERNAL transcription factors of the gap, pair ruled and other early
patterning genes. This explains the fact that some parts of the embryo (those
expressing the string) will grow faster than others.
The fact that maternal transcripts of of a hormone, retinoic acid (RA) and its
receptors are detected during early development and the fact that expression of
almost all the homeobox genes is controlled by RA suggest that the maternal RA
is crucial for early embryonic patterning and establishment of the
antero-posterior axis during gastrulation. MATERNAL factors of the dorsal
region (growth factors of the TGF-beta superfamily, Vr1, and activin) also act
as signals for inducting mesoderm formation and the Nieuwkoop center.
Maternal Control of Early Development in Mammals
The intimate maternal-embryonic contact during all stages of embryonic
development in mammals allows an immediate regulation of the embryonic
development by maternal neuroendocrine system. This explains the fact that the
role of maternal cytoplasmic factors in the early development of mammals
terminates considerably earlier than other groups of metazoans (whereas in
Xenopus, the expression of the zygotic genes starts first in the ~5,000-cell
embryo, the embryonic genome of the mouse starts expressing zygotic genes as
early as the one-cell stage).
In preparation for implantation, numerous growth factors are expressed in the
maternal reproductive tract (Hardy and Spanos, 2001). So, e.g., the endometrium
expresses 22 genes for growth factors at the site of blastocyst attachment
(Paria et al., 2000); their expression ultimately is under control of the
maternal CNS. The expression of the epidermal growth factor (EGF) in the pig
oviduct is stimulated by estradiol, a downstream element of a signal cascade
that starts with an epigenetic brain signal that is communicated to the ovary
via hypothalamic-pituitary axis. The same is valid for a number of other growth
facytors expressed in preimplantation uterine tissues, such as amphiregulin
(Giudice, 1999), beta-cellulin and epiregulin (Das et al., 1997) and cytokines
such as leukemia inhibitory factor, macrophage colony-stimulating factor,
interleukin-1, hepatocyte growth factor, and insulin-like growth factors
(Giudice, 1999; Kauma, 2000), etc. etc.
During the blastula stage, the mouse extraembryonic ectoderm expresses Mmp-4,
which is necessary for the formation of primordial germ cells as well as for
determining the size of their population and formation of allantois.
Secretion of most of the secreted proteins that participate in the preparation
of the endometrium for implantation is hormonally regulated. But, in view of
the fact that neuroendocrine regulation of expression of secreted proteins is a
general mode of regulation and that the endometrium is "the end organ of the
hypothalamic-pituitary-ovarian axis." (Tabidzadeh, 1998), it seems reasonable
to predict that the rest of them as well are hormonally regulated.
In mice, the transplacentally provided maternal estradiol upregulates
expression of the zygotic Wnt1 gene during the morula-blastula transitional
period. The fact that growth hormone receptor mRNA is expressed in
preimplantation bovine embryos and growth hormone (GH) favorably affects their
cleavage and blastocyst formation suggests that GH, which is cerebrally
regulated by hypothalamic GHRH (growth hormone releasing hormone), plays an
essential role in regulation of the preimplantation development in bovines.
The maternal neurotransmitter serotonin reaches the embryo transplacental and
plays important roles in the development of notochord, somites, neural crest
(Moiseiwitsch and Lauder, 1995), cranio-facial mesenchyme and epithelia
(Lambert and Lauder, 1999), heart (Nebigil et al., 2000), heart myocardium
(Lauder and Zimmerman, 1988) etc. The neurotransmitter dopamine plays a role in
placental function in humans (Villancourt et al., 1998). Serotonin is involved
in the regulation of the cranial neural crest migration as well as in the
formation of the heart and neural tube.
Formation of the Embryonic Germ Layers
Formation of endoderm is determined not by the genetic information (zygotic
genes) but by the epigenetic information maternally deposited in the egg in the
form of cytoplasmic factors of three main groups : VegT, beta-catenin, Otx and
eomesdermin (Grapin-Boton and Constan, 2004).
Formation of mesoderm also is EPIGENETICALLY induced by maternal VegT, which
controls and regulates expression of zygotic growth factors of TGF-beta
superfamily (Nodal subfamily), Xnr1, Xnr2, Xnr4 and derriere. (Kofron et al.,
1999; Clements et al., 1999; Kimmelman and Bjornson, 2004).
Formation of the Central Nervous System (CNS)
In Xenopus, maternally provided epigenetic information starts the neural
induction and specifies neural cells as early as the blastula stage (Wilson and
Edlund, 2001), i.e. before the gastrulation and large-scale expression of
zygotic genes (12th cell division cycle or 4096-cell embryonic stage). Maternal
epigenetic information determines formation of the Nieuwkoop center (Stennard
et al., 1996) and activation of downstream zygotic genes (Yang et al., 2002),
which stimulate cells dorsal to the Nieuwkoop center to from the Spemann's
organizer (Schneider et al., 1996; Laurent et al., 1997). The latter releases
signals for the formation of neuroepithelium and the neural plate from which
all neurons and glial cells derive (Dowling, 2004).
So, the early development in all groups of animals considered is under control
of the maternal epigenetic information deposited in the egg in the form of
maternal cytoplasmic factors (as shown in the first article, this deposition is
regulated by the maternal CNS). Expression of zygotic genes in space and time
is determined by that epigenetic information until the phylotypic stage.
Formation of the central nervous system during the phylotypic stage reveals
some thought-provoking facts:
1. While the conventional wisdom says that systems of blood circulation (supply
of oxygen and nutrients) and excretory systems would be necessary to develop in
the embryo before all else, it is the nervous system the first organ system to
develop, even though the communication of the embryo with the external world is
minimal. One would wonder why?
2. Initially, the CNS is excessively large (in some cases representing a
quarter of the overall embryonic mass), what again cannot be related to the low
level of communication of the embryo with the external environment.
3. Formation of the functioning CNS at the phylotypic stage coincides with the
exhaustion of the maternal epigenetic information (maternal cytoplasmic
factors).
4. The incipient CNS immediately starts "a network of inductions that give rise
to the different cells, tissues and organs of embryos and adults." (Hall, 1998)
All the above facts point in the direction of an essential role of the
embryonic CNS in the postphylotypic development, i.e. after the exhaustion of
the maternal epigenetic information (cytoplasmic factors). Indeed, adequate
experimental evidence also shows that, after the phylotypic stage, the CNS is
the source of the epigenetic information for activating signal cascades for the
development of organs and morphology in metazoans. This evidence will be
presented in the next article.
Nelson R. Cabej
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