Epigenetic Control of the Postphylotypic Development

Epigenetic Control of the Postphylotypic Development

At the phylotypic stage the reserve of epigenetic information in the
animal embryo is exhausted. This moment of “epigenetic informational
crisis” coincides with the formation of the operational CNS, which
takes over the post-phylotypic development in metazoans. It initiates

“a network of inductions that give rise to the different cells,
tissues and organs of embryos and adults.” (Hall 1998. p. 131)

The neural origin of information for postphylotypic development is
unquestionably demonstrated for coelenterates (Schwoerer-Bohning et
al. 1990), molluscs (Leise et al. 2001), and insects (Baehrecke
1996). Therefore, I will only present a few examples to illustrate
the fact that, as pointed out by the distinguished evolutionary
developmental biologist B.K. Hall:

“further structures arise in relation to this central axis. This is
especially evident in the development of paired elements such as the
somites that presage the vertebrae, and paired organ rudiments such as
left and right limb buds and the primordia of the gonads, kidney, lung
heart” (Hall, B.K. 1998. Evolutionary Developmental Biology, 2nd
edition. London: Chapman & Hall, 114-119. p. 163).

The central neural control of individual development is also
recognized by other authorities in the developmental biology:

“Perhaps the most interesting thing about having a hormonal regulation
of development is that development comes under the control of the
central nervous system.” Nijhout, H.F. (2003. Development and
evolution of adaptive polyphenisms. Evolution & Development 5: 9–18)

(I will discuss the epigenetic nature of developmental information in
the next post of this series).

Epigenetics of somitogenesis and myogenesis

The expression of beta-catenin mRNA in somites is regulated by
positive and negative signals (BMP4, Shh, and Wnt/Wnt3) secreted from
the neural tube (Schmidt, M. et al. 2000. Development 127:
4105-4113). Within somites, the myogenesis is also induced by neural
tube signals, such as Wnt-1 that may induce expression of Noggin, a
BMP antagonist, which may stimulate myogenesis by allowing expression
of MyoD and Myf5 in somite cells (Reshef, R. et al. 1998. Genes &
Development 12: 290-303). In chicken embryos, motor neurons while
entering the limbs, release the RA generating, RALDH-2 enzyme,
inducing there muscle cell differentiation and muscle formation
(Berggren, K. et al. 2001. Developmental Biology 210: 288-304).
In Drosophila, local innervation is directly and crucially involved in
the proliferation and distribution of myoblasts and myogenesis
(Currie, D.A. and Bate, M. 1991. Development 113: 91-102). So, e.g.
unilateral denervation of dorso-ventral muscles (DVMs) controls muscle
fiber differentiation during myogenesis, leading to the failure to
form muscle Anlagen and muscles.

“The motoneuron influences both the number of cells available for
fusion, as well as potentially regulates the fusion events themselves.
This in our view is an elegant mechanism for controlling muscle fiber
differentiation during myogenesis, and may have evolved as a way to
ensure that muscle primordia develop into muscles that meet the
diverse demands placed on them by the nervous system.” (Fernandes,
J.J. and Keshishian, H. 2005. Developmental Biology 277: 493-505)

Neurectomy of the larval leg nerve before metamorphosis in the moth
Manduca sexta prevents proliferation and normal migration and
accumulation of myoblasts in respective regions, so that in 26% of
cases no muscles develop in adult legs (Consoulas, C. and Levine, R.B.
1997. Journal of Neurobiology 32: 531-553).

The failure of the abdominal intersegmental muscles in the saturniid
silkmoths takes place in the presence of hormone ecdysone and in the
absence of JH (juvenile hormone) and investigators have concluded that
“The actual breakdown is triggered by a neural mechanism. The latter
consists of a sudden curtailing or cessation of the outflow of
impulses in the motor nerves which innervate the abdominal muscles… By
chronic electrical stimulation of the nerves, the breakdown of the
muscles can be opposed or prevented.” (Lockshin, R.A. and Williams,
C.M. 1965. Journal of Insect Physiology 11: 601-610)

An essential relationship between the nervous system and myogenesis
has also been observed in vertebrates. The differentiation of
myoblasts, which starts the development of skeletal muscles within
somites, depends on the expression of MyoD genes (Alves et al., 2003.
2003. Brazilian Journal of Medical and Biological Research 36:
191-197) coding for transcription factors that induce expression of
genes for muscle specific proteins (MSPs) (Alves, H.J. et al.,
2003.Ibidem; Te and Reggiani, 2002). Again, signals for expression of
MyoD genes (among them, Hedgehog and Wnt) originate in the neural tube/
notochord adjacent to somites (Te, K.G. and Reggiani, C. 2004. Journal
of Muscle Research and Cell Motility 23: 65-69). Experimental
misexpression of Myf5 and MyoD in the chick neural tube results in
ectopic skeletal muscle development (Delfini, M-C. and Duprez, D.
2004. Development 131: 713-723).
Studies on the development of muscles in the paraxial mesoderm (on
both sides of the neural tube) and somites in chicks have shown that
signals from the adjacent dorsal neural tube, and to a limited extent
from the ventral neural tube, are basic inducers of myogenesis in the
embryo. Ablation of the neural tube prevents formation of muscles in
these structures (Stern, H.M. et al., 1995. Development 121:
3675-3686).
The central nervous system controls and regulates the development of
target muscles not only directly, via peripheral nerves, but also
indirectly, by long-range action, via the neurohormonal signal
cascades. Often, both modes of control are operational in the
development of the same muscles, giving rise to a binary neural
control of myogenesis. This is the case, e.g., with the development of
the laryngeal muscle in Xenopus laevis. In juvenile animals, the
laryngeal muscle is similar, female-like, in both sexes. After
metamorphosis, as a result of androgen secretion, male individuals
develop the male-specific muscle. Denervation of the muscle, however,
causes its atrophy in male amphibians, whereas androgen administration
causes its hypertrophy (Tobias, M.L. et al., 1993. Journal of
Neuroscience 13:324-333).
It is worthwhile to note that the laryngeal nerve, under normal
conditions, may be involved in the effects produced by the androgen
since both laryngeal muscle and motoneurons, after metamorphosis,
express androgen receptor. Experimental evidence has shown that

“The nerve is required for maintenance of existing fibers and
denervation results in cell death.” (Tobias et al., 1993, Ibidem)

The development of the dorsal external oblique 1 (DEO1) muscle in
Manduca sexta also is function of a binary neural control mechanism;
on the one hand, it is mediated via the cerebral PTTH
(prothoracicotropic hormone)-ecdysone axis and, on the other, it is
carried out via local innervation. 

Epigenetics of the Development of Endocrine Glands

The pituitary Anlage is induced by BMP4 and FGF8 signals from
neuroepithelium of the adjacent diencephalon (Takuma, N. et al. 1998.
Development 125: 4835-4840; Treier, M. et al. 2001. Development 128:
377-386), or infumdibulum (extension of the third ventricle of the
brain to the pituitary). Later, another cerebral signal FGF8, from the
diencephalon (consisting mainly of thalamus and hypothalamus),
combined with a BMP2 signal from a ventral pituitary organizing center
induces the second step in the embryonic development of the
pituitary . Brain secretion of FGF8 activates homeobox genes Lhx3 and
Lhx4 (Sheng, H.Z. et al., 1997. Science 278:1809-1812). In the third
stage of the pituitary development, suspension of BMP2 signal from the
diencephalon allows differentiation of various pituitary hormone-
secreting cells (Treier, M. et al., 1998. Development 128: 377-386).
The ventral diencephalon also provides growth factors of the Fgf
family, especially Fgf3, which are involved in specification of the
progenitor cells of the adenohypophysis and formation of the
adenohypophyseal Anlage (Herzog, W. et al., 2004. Development 131:
3681-3692).
Development of the thymus, as a typical example of neural control of
organogenesis, depends on the right balance of two hypothalamic
hormones, growth hormone releasing hormone (GHRH), and growth hormone
releasing inhibitory hormone (GHRIH) (Hirokawa, K. et al. 1998.
Mechanisms of Ageing and Development 100: 177-185. ; Hirokawa, K. et
al. 2001. Cellular and Molecular Biology 47: 97-102).

Epigenetics of kardiogenesis

The neural tube sends signals (Wnt3 and Wnt8) that inhibit induction
of kardiogenesis along the whole of its length, except for the region
where the heart normally develops. It has been possible to induce
ectopic heart formation in other parts of the body by simply
activating the GSK3 or other Wnt antagonists (Schneider, V.A. and
Mercola, M. 2001. Genes & Development 15: 301-304.;Tzahor E, and
Lassar AB, 2001. Genes & Development 15: 255-260).

Besides the role of the neural tube inductions, an essential role in
the development of the kardiovascular system, play neural crest cells
that migrate from the neural tube to participate in the formation of
the heart. The region of the neural crest that is involved in the
process is known as cardiac neural crest and is located between the
mid-otic placodes and the caudal limit of the somite 3 (Kirby et al.
1993). The cardiac neural crest cells that migrate to the heart region
initiate the formation of the outflow tract and the smooth muscle of
the aortic arches (Phillips MT. Et al. 1987. Circulation Research 60:
27-30; Creazzo, T.L. Et al. 1998. Annual Review of Physiology 60:
267-286).

Epigenetics of Vasculogenesis and Angiogenesis

The processes of vasculogenesis (formation of a primary network of
capillaries or vascular plexus) and the differentiation of endothelial
cells from their precursors take place approximately at the time that
the embryonic heart starts to develop. During embryogenesis, the
sensory neurons secrete VEGF, which determines the cell
differentiation and patterning of arteries in their vicinity
(Mukoyama, Y. et al. 2002. Sensory Nerves Determine the Pattern of
Arterial Differentiation and Blood Vessel Branching in the Skin. Cell
109: 693-705). This explains the old anatomic observation on the
general association of arteries and peripheral nerves. A group of 5
vascular endothelial growth factors (VEGFs), as well as FGF-2, are
involved in vasculogenesis and angiogenesis (Liang. D. et al. 2001.
Mechanisms of Development 108: 29-43); all of them are downstream
elements of signal cascades originating in the CNS.

“Peripheral nerves provide a template that determines the organotypic
pattern of blood vessel branching and arterial differentiation in the
skin, via local secretion of VEGF.” (Mukoyama,Y. et al., 2002. Cell
109: 693-705)

It is demonstrated that in coculture with presomitic mesoderm, the
neural tube is able to induce formation of a perineural vascular
plexus. Based on the demonstrated roles of the neural tube in vascular
patterning, the neural tube is considered to be the midline signaling
center for vascular patterning in higher vertebrates. (Hogan, K.A. et
al., 2004. Development 131: 1503-1513).

Epigenetics of the Development of the Gastrointestinal Tract

The specification of different parts of this tract is related to the
spatio-temporal pattern of expression of various Hox genes along the
embryonic antero-posterior axis. But the ordered expression of Hox
genes during the embryonic development in vertebrates is regulated by
the hormone retinoic acid (RA). The neural tube, which is adjacent to
the gastrointestinal endoderm is an important source of the RA for the
development of the gastrointestinal tract.
In chick embryos, the neural tube/spinal cord in its length up to the
hindbrain has the highest levels of RA. The neural tube/CNS is also
crucially involved in the development of the gastrointestinal tract in
another direct way. Migratory cells from the neural tube reach the
region of the prospective gastrointestinal tract and participate in
the development of the organs of the tract.

Epigenetics of lung development

RA and the hormonally induced EGF have a stimulating effect on lung
development while DHT (dihydrotestosterone) is an inhibitor. In
humans RA “is indispensable for the formation of primary lung buds and
the oesophago-tracheal septum.” (Mollard, R. et al. 2000.
International Journal of Developmental Biology 44: 457-462).
The production of the surfactant (a mixture of proteins and
phospholipids that is essential for survival at the time of birth)
results from a cerebral cascade: hypothalamic CRH--> pituitary
corticotropin --> adrenal cortisol--> the fibroblast pneumocyte factor
(secreted by lung fibroblasts)--> surfactant (secreted by type II
pneumocytes).

Epigenetics of nephrogenesis

Since the early 50s, C. Grobstein observed that explants of the mouse
embryonic spinal cord, separated from metanephrogenic mesenchyme by a
cell-nonpermeable filter induced formation of kidney tubules in the
mesenchyme (Grobstein, C. 1956. Experimental Cell Research 10:
424-440).

In vitro experiments have shown that when nephrogenic mesenchyme is
separated from various embryonic tissues by a membrane filter, of all
the tissues tested for induction of nephrogenesis

“only embryonic spinal cord and brain were effective whereas the
ureter bud did not induce... These studies suggest that embryonic
neurons are the most effective inducers of nephrogenic mesenchyme in
vitro.” (Sariola, H. et al. 1989. Developmental Biology 132: 271-281)

Epigenetics of the Development of Reproductive Organs

It was discovered, years ago, that activation of the sex-determining
gene, Sry, in the Y chromosome during early embryogenesis starts
sexual differentiation in mammals. We are now told that the Sry gene
is itself a downstream element in the insulin-signaling pathway. It
has been demonstrated that of the 12,000 genes expressed in the
embryonic brain of mice, at least 7 show differential expression in
brains of male and female mice “before any gonadal hormone
influence” (Dewing, P. 2003. Brain Research Molecular Brain Research
118: 89-90), which clearly suggests that sexual differentiation is not
hormonally determined by gonads but centrally, by the CNS.
Furthermore, the transplantation of female forebrain primordium into
male embryos before gonadal differentiation prevents the
differentiation of male sex organs in genetically male embryos (Gahr,
M. 2003. Proceedings of the National Academy of Sciences USA 100:
7959-7964).

Epigenetics of Environmentally Determined Sex

In many reptiles, sex is determined by the environmental temperature:
the embryonic brain perceives the temperature, processes and converts
it into a signal, that induces expression of aromatase (Milnes MR et
al. 2002. Environmental Health Perspective Suppl 3: 393-396), which in
turn converts androgens into estrogen.
In the sea turtle Lepidochelys olivacea, it is the diencephalon, not
the gonads, that starts sexual differentiation by responding to the
female-promoting temperature with elevated estradiol levels, and it is
the diencephalonm that senses temperature for sex determination
(Salame-Mendez, A. et al., 1998. Journal of Experimental Zoology 280:
304-313). Still undifferentiated gonads of the sea turtle are pervaded
by acetylcholinesterase-positive nerve fibers from spinal cord during
the thermosensitive period of sex determination and it is suggested
that

“The spinal cord and the innervation derivating from it could play a
role in driving or modulating the process of temperature-dependent
gonadal sex determination and/or differentiation.” (Guiterrez-Ospina,
G. et al. 1999. Journal of Comparative Neurology 410: 90-98).
In many insects, transplantation of male brains alone into female
abdomens induces presumptive ovaries to develop male secondary sexual
characters (Gorbman, A. and Davey, K. 1991. Endocrines. In:
Neural and Integrative Animal Physiology. 4th edition Wiley-Liss. p.
733).

Epigenetics of Sex Conversion in Fish

Sex conversion defies the notion that genetic factors (genes or sex
chromosomes) are the exclusive determinants of sex in animals. Sex
conversion in fishes is determined by social factors, and is
associated with radical changes in the direction of the opposite sex
in morphology, morphometry and behavior of convert fish. These changes
in either direction may be permanent or reversible in matter of
minutes.
Under the influence of changed social environment and behavior,
teleost fish change sex within their lifetime. Based on the fact that
sex conversions (female-->male, and male-->female) in teleost fish
occur regardless of the absence or presence of the chromosome Y, but
depend on the increase and decrease in the number of GnRH-secreting
neurons, it is concluded that “the only way behavior could affect the
gonads is through the brain.” (Elofsson, U. et al. 1997. In:
Experimenttal Biology Online).
Sex conversion in fishes is determined by a central neural mechanism
(modification of electrical properties and of the the size of
hypothalamic GnRH (gonadotropin-releasing hormone) neurons and
specific neurons in the forebrain.

“Such changes in the POA GnRH cell population phenotype may reflect a
proximate central mechanism in the induction of dramatic gonadal and
behavioural transformations that are associated with sex change in
hermaphroditic fish.” (Elofsson U. et al. 1997. Journal of Comparative
Physiology A 181: 484-492)

Commenting on the mechanism of sex conversion, experts have concluded
that

“The initiation of the sex reversal is often controlled by social,
behavioural factors, and since the only way behaviour can affect the
gonads is through the brain, there must be central neuronal
mechanisms underlying the gonadal change (Elofsson et al. 1997.
Experimantal Biology Online. The Society for Experimental Biology
Annual Meeting. University of Kent at Canterbury, 7-11 April 1997.
A8.20. Abstracts).

Epigenetics of Bone Development

Bone formation is under the control of signal cascades that ultimately
originate in the CNS.
Studies on the relationship between the hormone leptin and bone
formation in mammals have led investigators to the conclusion that
leptin carries out its antiosteogenic action via the CNS (Ducy et al.
2000). Experimental evidence shows that the regulation of bone mass by
leptins is not hormonal; leptin does not act as a hormone on
osteoblasts but as a feedback signal in the brain. It binds to its
receptors in hypothalamic neurons, which after processing this signal,
respond by releasing a neural signal that stimulates the peripheral
sympathetic system, whose beta-adrenergic signals bind to osteoblast
beta-receptors and inhibit their proliferation (Takeda, S. et al.
2002. Cell 111: 305-317.).
Bone homeostasis as well is under central control. Changes in bone
loading are source of mechanosensation in specific CNS centers, where
the sensory information is integrated and processed. The CNS then
determines activation of appropriate signal cascades for all the
processes of bone remodeling “from normal remodeling to fracture
healing and non-union” and

“Bone nerves/neuropeptides may explain why various inputs/outputs are
transformed in a meaningful way to altered mass and quality of
bone.” (Konttinen, Y et al. 1996. Acta Orthopedica Scandinavica 67:
632-639 (Abstract))

Epigenetic control of the body mass

H.F Nijhout has argued that

“Although the genetic or experimental alterations of a cellular
mechanism that controls cell division, or cell size, can alter organ
or body size, this does not imply that that this mechanism controls
organ or body size, as is often suggested. Such a cellular mechanism
must be a downstream component of a regulatory cascade whose control
(that is, the origin of the difference that determines whether to
grow or stop growing) resides at a higher level.” (Nijhout, H.F.
2003. Developmental Biology 261: 1-9)

Body size in Drosophila is regulated by seven median secretory neurons
in pars intermedialis of the protocerebrum. Ablation of these neurons
prevents the growth of the fly with symptoms of starvation phenotype
(Ikeya, T. et al. 2002. Current Biology 12: 1293-1300).

In experiments with deer mouse (Peromyscus maniculatus),
intraperitoneal implantation of metabolically inert masses causes a
compensatory and equivalent loss of body weight. Then, in the 12th day
after the removal of the implant the animals regain the pre-
experimental body weight. The investigators argue that the changes in
the body weight “suggest the existence of a set point that is
sensitive to changes in the perception of mass and that is transduced
via neural pathways.” They argue that numerous mechanoreceptors
located within muscles and tendons that have afferent pathways to
cerebral cortex could provide the input on the body mass (Adams, C.S.
et al. 2001. Journal of Experimental Biology 204: 1729-1734.).
Pentaploid salamanders’ cells have five times the volume of the cells
of haploid species and yet these animals have approximately the same
size because the pentaploid species have ~3 times less cells in their
body (Alberts, B. et al. 2002. Molecular Biology of the Cell. 4th
Edition. New York: Garland Science, pp. 1023-1024.). This clearly
implies the existence of set points for the normal number of cells or
for the body mass as well as a mechanism for monitoring the actual
state, comparing it with the set point for the “normal mass”, and
sending messages (via signal cascades) for restoring or maintaining
the “normal state”.

Epigenetics of Mammogenesis

Although mammals are born with a mammal anlage, the gland develops
predominantly after the puberty and post partum. “The entire
developmental program, mimicking embryonic development of other
organs, can be viewed and followed in the post partum
animals” (Hennighausen, L. and Robinson, G.W. 1998. Genes &
Development 12: 449-455). The formation of the gland is under a
complex control of systemic hormonal signals from the hypothalamus
(prolactin releasing factor), pituitary (prolactin) and the ovary
(estrogen, progesterone). The signals are executed by local mediators,
Wnt (Sassoon, D. 1999. Molecular and Cellular Endocrinology 158:
1-5.), EGF, and TGF-beta proteins, VIP, TRH (Gilbert, S. 1997).

The developmental pathway starts in the CNS: in response to internal
signals, related to the activation of the hypothalamic GnRH pulse
generator and especially to gestation, neurons of the caudal part of
the solitary tract release a neuropeptide, PrRP (prolactin-releasing
peptide). Even the Gpr54 gene, the so-called “regulator of puberty”,
is no more than an element downstream the GnRH in the signal cascade
leading to puberty (Seminara, S.B. et al. 2003. New England Journal of
Medicine 349: 1614-1627).

Experiments in guinea pigs suggest that the sympathetic nerves
innervating the ovary also contribute in the appearance of puberty by
regulating the follicular growth, oocyte maturation, and atresia
(Riboni et al. 1998).
In response to activation of the GnRH pulse generator, neurons of the
solitary tract release the prolactin-releasing peptide (PrRP) and
other areas of the brain send signals activating a dopamine circuit in
the hypothalamus, which responds by secreting gonadotropin-releasing
hormone (GnRH) and prolactin-releasing factor (PRF). These releasing
hormones stimulate secretion of gonadotropins and prolactin
respectively. Downstream, these hormones stimulate the ovary to
secrete estrogen and progesterone. Prolactin induces expression of wnt
in the mammary cells. Estrogen, via EGFR (epithelial growth factor
receptor) pathway and by inducing expression of IGF1 (insulin-like
growth factor 1), and progesterone via its PR (progesterone receptor),
stimulate cell growth and ductal outgrowth in the gland.

Epigenetics of Apoptosis

Apoptosis is an evolutionarily old mechanism of the elimination of
excess cells with indispensable functions in sculpting animal organs
and general morphology during embryogenesis and later individual
development.
Apoptosis of the salivary gland in Drosophila is result of a signal
cascade that starts in the fly's brain. In response to internal and
external stimuli the CNS secretes neuropeptide PTTH
(prothoracicotropic hormone), which induces the prothoracic gland to
secrete ecdysone. The latter, via its receptor EcR, induces expression
of the primary response genes BR-C, E74A, and E93 (Lee, C. and
Baehrecke, E.H. 2001. Development 128: 1443-1455; Yin, V.P. and
Thummel, C.S. 2004.Proceedings of the National Academy of Sciences USA
101: 8022-8027). Products of these genes induce apoptotic genes
reaper and hid.
In Xenopus, a maternal cell death program is activated at a maternally
determined checkpoint as early as the midblastula stage (Hensey, C.
and Gautier, J. 1999. Annals of the New York Academy of Sciences 887:
105-119 ; Sible, J,C. et al. 1997. Developmental Biology 189:
335-346) if the expression of zygotic genes does not occur or is
delayed. The program compensates for the lack of cell cycle
checkpoints in the pre-midblastula transition embryos (Hensey and
Gautier, Ibidem, 1997). During amphibian metamorphosis, the thyroid
hormone (T3) regulates tail regression in tadpoles by activating
expression of the Bax gene, which stimulates apoptosis of tail
myocytes (Sachs, L.M. et al. 1997. FSSEB Journal 11: 801-808).

The pituitary hormone, prolactin, is reported to induce apoptosis in
the penultimate stage of the spermatogonium in newt by activating an
unidentified caspase (Yazava et al. 2001). Apoptotic elimination of
ovarian germ cells and degeneration of ovarian follicles in rats
involves caspase-3 and caspase-7, but the expression of the respective
genes is regulated by the pituitary hormones, LH and FSH, that are
themselves under cerebral control of the hypothalamic GnRH (Yacobi et
al. 2004).

The above examples prove that the CNS origin of signal cascades is not
only haphazardous (no other organ or organ system has been shown to
control the development of other organs) but essential for individual
development in metazoans.


N.C.





.

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