Maternal factors present in the cytoplasm of the egg cell include maternal transcripts (mRNAs) of most important genes, such as cyclins, which determine the first cleavage divisions, hence are among the earliest maternal transcripts to be translated. Other maternal factors induce expression of genes for the synthesis of neurotransmitters, and this takes place very early at the blastoderm stage.

Three systems of maternal transcripts (bicoid mRNA, nanos mRNA, caudal mRNA, and hunchback mRNA) determine the establishment of the anterior-posterior axis in insects. In insects, most of these these transcripts that come into the egg cell from nurse cells, initiate a transcription sequence of zygotic genes (gap-pair ruled-engrailed-homeotic).

In vertebrates, the first divisions of the zygote are stimulated by translation of the maternal Cdc6 mRNA, which makes possible the replication of zygotic chromosomes by activating the MCM (minichromosome maintenance) helicase complex (Lemaitre et al., 2002).

Where the sperm cell enters the egg cell, it induces the cortical reaction, characterized by accumulation of a number of maternal cytoplasmic transcripts (beta-catenin-, Wnt-, Vg1-, Xwnt11-, Noggin-, and Activin mRNAs) determining, thus, formation of the dorsal side of the future embryo. Signals that induce mesoderm formation also are maternal cytoplasmic factors of the dorsal region, probably FGF2 (fibroblast growth factor 2) and BMP4 (bone morphogenetic protein 4). To this group also belong maternal mRNAs for growth factors of the TGF-beta superfamily of secreted proteins, Vg1 and activin. The activin type II receptor is expressed in all the blastula cells and a number of maternal TGF-beta growth factors, including Vg-1, may bind it. Maternal RA (retinoic acid) is present in bovine oocytes during all stages of their development. Via its receptors, RA regulates expression of Hox genes, which have RARE (RA response elements) in their enhancers and are involved in establishing the anterior-posterior axis during early gastrulation in vertebrates.

Maternal cytoplasmic factors also play an essential role in the early development of mammals but, in distinction from other groups of animals, the placental mode of reproduction enables them to exert an additional, “real time” maternal control on the embryonic development. In preparation for implantation of the blastocyst, at the site of blastocyst attachment to the endometrium, the latter expresses 22 genes for growth factors (Paria et al., 2001), whose induction is under the ultimate maternal CNS control. In mice, EGF (epidermal growth factor) induces expression of its receptor, EGFR, as early as the 8-cell stage blastocyst (Kim et al., 1999). EGF is also expressed in oviducal and endometrial membranes of pregnant pigs during the preimplantation period. This, and the fact that EGFR is also present in the zygote, suggests that maternal EGF is active in the blastocyst at this early stage. A maternal neurotransmitter, serotonin, plays an important role in mouse neurogenesis and on the formation of serotonin circuitries in the CNS where it may act as a “differentiation signal” (Lauder et al., 1981).

The early embryonic development ends at the phylotypic stage, at a time when the parental epigenetic information in the form of cytoplasmic factors is exhausted. Temporally, the consumption of maternal cytoplasmic factors coincides with the emergence of the functioning CNS at the phylotypic stage. At this point in time, the CNS is capable of rising to occasion: to generate and provide epigenetic information for molding the extraordinarily complex species-specific structures and organs that develop after the phylotypic stage.

The embryonic operational CNS, with established circuits, is capable of neural computation. By computationally determining the release of electrical/chemical signals for starting specific signal cascades, it starts a long series of inductive events, all over the embryonic structure, stimulating the development of all the tissues, organs and other parts, the whole metazoan morphology. After the phylotypic stage, to the CNS goes the lion’s share, if not the whole, of the inductions determining the development of metazoan morphology.

These crucial functions of the CNS as inducer of the development of all the organs and organ systems in metazoans may also account for its puzzling overearly emergence during the individual development. These functions may be the reason why the CNS (whose main function is considered to be communication with the external environment) is consistently the first organ system to develop in metazoans, although the blood circulation system and excretory system, related with nutritive and excretory functions, from the conventional physiological view would be required to develop before any other system. Its morphogenetic functions in the postphylotypic development might also account for the unproportionally large size of the embryonic CNS in early development.

The Embryonic CNS-Controlled Phase: The Postphylotypic Development

The phylotypic stage is a crucial moment in the individual development, when embryos of different species, no matter how different their initial development might have been, converge toward a recognizable common Bauplan, displaying the basic morphological features of the phylum. The phylotypic stage follows the early development and starts at a time when the parental epigenetic information in the form of maternal cytoplasmic factors is exhausted. This informational crisis unfolds at a critical moment: the postphylotypic development requires incomparably greater amount of information for morphogenetic processes (development of organs and other metazoan structures) than the early development does. Temporally, the informational crisis coincides with the emergence of the functioning CNS at the phylotypic stage, which appropriately responds to the input of data from the developing embryonic structure, with “spontaneous” electric activity, necessary for setting up neural circuits, for modifying their synaptic morphology (Peinado, 2000; Zhang and Poo, 2001) and sequentially generating the information necessary for successive stages of the development.

The enormous amount of information necessary for establishing these circuits and specific neuronal connections is not inherited parentally, via gametes. The parental epigenetic information in the form of cytoplasmic factors controls the development of the initial structure of the CNS (and probably the assembly of the initial neural circuits) at the phylotypic stage. The epigenetic information for the development of post-phylotypic structures is not inherited. What the embryo parentally inherits is not an epigenetic program but an antientropic contrivance that is the CNS, which is capable of computationally generating the epigenetic information necessary for the post-phylotypic development based on its interaction with the developing embryonic structure. Essentially, this interaction consists in the processing of the afferent input (spontaneous electrical activity) from the developing embryonic structure according to the brain’s ”best guess” (Katz and Shatz, 1996) based on the “self-organizing properties” (Weliky, 1999) of the nervous system. In the absence of afferent input on the actual embryonic structure, normal neural circuits are not formed (Penn et al., 1998) and rat striatal neurons do not develop dendritic spines (Segal et al., 2003). Empirically it is demonstrated that disruption of that input from reaching the CNS (via denervation or otherwise) may fully or partially prevent the  embryonic development of corresponding  embryonic structures.

At the time of birth the vertebrate embryo has established an estimated 70-80% of trillions of nonrandom, specific neuronal connections it will have as an adult organism.

The operational embryonic CNS at the phylotypic stage is developmentally self-reliant, and takes over the postphylotypic development. By processing the input of internal and external stimuli in neural circuits, it generates its output in the form of chemical signals, which represent information that via signal cascades, or via the nerve endings, is communicated to various parts of the developing embryo for inducing expression of specific genes and cell differentiation. This epigenetic information induces the development of tissues (muscle, bone, adipose, etc.), organs (heart, endocrine glands, gastrointestinal tract, liver, lungs, kidneys, gonads, etc.), and related developmental phenomena, such as directed cell migration, programmed cell death, left-right asymmetry, etc.

Additionally, in vertebrates the CNS expanded its organogenic functions by evolving a do-it-yourself mode of operation. The novel structures performing that function are the neural crest and VENT cells, which form on (and from) the embryonic neural tube/CNS and. Neural crest cells leave the CNS early during embryogenesis and migrate to precisely determined sites throughout the animal body, to contribute to the development of most of the vertebrate tissues, organs and structures. Before leaving the neural tube/CNS and starting their migration, neural crest cells are provided with epigenetic information for  finding their way to specific sites of migration and for transforming themselves as well as cells in the target sites, into cell types characteristic for the organs they give rise to.

In the process of post-phylotypic development, the embryonic CNS in vertebrates extensively uses neurohormonal mechanisms along the hypothalamic-pituitary-target glands. The CNS also performs inductive/suppressive functions in targeted regions of the body, via inducers released by local nerve endings of the peripheral nervous system in order to restrict the action of hormones in specific organs and parts of the body.

The Binary Neural Control of Gene Expression

Ultimately, genes are the mediators of all the  morphogenetic functions of the CNS in the postphylotypic development and most of signal cascades originating in the CNS via neuroendocrine pathways result in expression of a gene, group of genes or even gene regulatory networks.

Hormones released at different levels of the  brain-hypothalamic-pituitary-target endocrine glands axes (and other axes), as well as other inducers, via body fluids, circulate throughout the animal body. Hence, the neurohormonal control per se, i.e. without another complementary mode of control, would be inappropriate for the development of metazoan structures requiring targeted action of these inducers in specific sites of the animal body.

The fact that hormones and other inducers, while circulating throughout the animal body, display inductive activity only in particular regions of the animal body, while the rest of the regions of the body remain insensitive to their action, suggests that metazoans have evolved a mechanism for targeted action of these inducers in the animal body.

Besides the above spatially restricted action of  inducers in the animal body, a temporal correlation has been observed to exist between the secretion of some morphogenetically crucial hormones and the sensitization of target tissues to them:

It is as if tissues somehow “know” when the hormonal signal will come and become receptive to it only at that time. (Nijhout, 1999)

Hormones perform their activities by binding to specific membrane or nuclear receptors in a process that triggers activation of signal transduction pathways or nuclear factors, with expression of specific genes as end result. Hence, the theoretical possibility exists that animals could spatially restrict the action of hormones in target sites by simply expressing specific receptors for hormone receptors in these sites alone, while preventing their expression in the rest of the animal body. Adequate experimental evidence shows that this is the case: sensitization of the target tissues to hormones results from expression of specific hormone receptors in the target cells and tissues, but not in other parts of the body.

The temporal correlation of expression of hormones and their specific receptors in particular regions of the body is not self-explanatory: the fact that only target cells express the respective hormone receptor, suggests that the information necessary for secretion (not the synthesis) of the hormone and expression of its specific receptor in target cells alone may ultimately come from the same source.

Indeed, it is known that the synthesis and secretion of a key insect hormone, the ecdysteroid, is regulated by a neurohormone, PTTH (prothoracicotropic hormone) produced in the insect’s brain. But there is also evidence that the targeted expression and secretion of the receptor  for the ecdysteroid hormone, EcR, in DEO1 (dorsal external oblique1) muscle in the moth, Manduca sexta, is regulated by corresponding motoneurons (Hegstrom et al., 1998).

The above is a universal mechanism of the  targeted action of circulating inducers in metazoans rather than an isolated example. Early in the course of their evolution, metazoans resolved the problem of selective restriction of the hormone action to particular  parts of the animal body at particular times by evolving a binary, humoral and adjacent, control of gene expression. In this control system the action of centrally induced signal cascades is permitted or prevented by the action of local nerve endings, which induce expression of specific hormone receptors only in target regions of the body.

The activity of this binary system of gene expression is demonstrated in well-established examples of myogenesis (Lawrence and Johnston, 1986; Currie and Bate, 1995; Bayline et al., 1998), osteogenesis (Goss, R.J. 1969h; Zeng et al., 1996; Edoff et al., 1997; Demulder et al., 1998), regeneration (Goss, R.J. 1969h; Hall, B.K., 1998k), puberty in mammals (Riboni et al., 1998), oogenesis in vertebrates (Morales et al., 1998), expression of receptors for pituitary LH (luteinizing hormone) in testicles (Lee et al., 2002), regulation of progesterone synthesis and reproductive physiology in humans (Fritz et al., 2001), secretion of estrogen and progesterone under influence of nervous fibers descending from the hypothalamus to the spinal cord, as well as sympathetic and vagal preganglionic neurons (De Bortoli et al., 1998), secretion of the juvenile hormone by corpora allata in insects (Stay et al., 1996; Kou and Chen, 2000), ovulation and determination of the number of deposited eggs in insects (Antkowiak and Chase, 2003), regulation of ecdysone synthesis by the neurohormone PTTH (prothoracicotropic hormone) and by direct neural control (Chapman, 1998d), the development of the laryngeal muscle in male Xenopus (Tobias et al., 1993), etc.

The adjacent control of gene expression is carried out by the peripheral nervous system, which via nerve endings establishes a ubiquitous presence all over the animal body, often down to the cell level. Nerve endings in specific regions of the body, by selectively inducing expression of specific hormone receptors are responsible for limiting the action of circulating hormones within the regions of prospective organs. Thus, the binary system of neural control of gene expression in metazoans prevents the indiscriminate action of circulating hormones and enables metazoans to restrict in space and time the action of hormones and other inducers. 

Solid empirical evidence demonstrates that, from the postphylotypic stage on, the embryonic CNS is systematically involved in the formation of all other organs and organ systems not only in its vicinity but throughout the animal body. However, the evidence on the control of organogenesis by the embryonic CNS deriving from experimental studies in the developmental biology and related fields raises a new and more difficult question: How does the embryonic CNS generate the epigenetic information necessary for erecting the metazoan supracellular structure?

Whereas an answer to this question is beyond the scope of this work, a modest attempt was made in chapter 2 to descriptively address this fundamental question based on the current knowledge on the generation and storage of information in the CNS. We have shown that this information is processing-dependent by origin, while the precise computational mechanisms determining the release of signals (information) that start developmental pathways for organogenesis remain to be determined.

Novel Features of the Epigenetic System of Heredity

Genetic (Watson-Crick) heredity determined by the genome, as exemplified in the reproduction of unicellular organisms, is also operative in the reproduction of individual cells in Metazoa and Metaphyta (Plantae). In the case of unicellular organisms the full amount of genetic (in some well-known cases also non-genetic) information for the two daughter cells is produced by the mother cell and provided to them in the process of cell division.

Metazoans as multicellular organisms, cannot rely for their reproduction on the template, replicative or Watson-Crick heredity alone, i.e. on transmission of genetic information for the synthesis of proteins. For, although proteins are necessary components of metazoans, their structural units or building blocks are not proteins but cells, billions and trillions of cells, arranged in strict spatial patterns requiring huge amounts of non-genetic information. As argued in chapter 1, the genetic information is qualitatively unsuitable for determining the relative position of cells in metazoans and quantitatively negligible compared to the amount of information necessary for building their multicellular structure.

The lack of the information for arranging the myriad of cells in specific spatial paterns from which the metazoan morphology arises represented a tremendous barrier for transition from unicellular life to metazoan multicellularity. This barrier stimulated a pressure for evolving a  ew type of information and an incomparably larger source of information. The solution came with evolution of a specialized structure capable of computating and generating the information for the multicellular metazoan structure as well as for transmitting it to the offspring. Crucial for the solution was the differentiation of the neuron and the nervous system.

This was a key evolutionary innovation that would enable parent(s) to communicate to the offspring only a part of the necessary information, i.e. information for the early embryonic development until the phylotypic stage, including the formation of the operational nervous system. At this juncture the embryonic and young nervous system takes over the further, postphylotypic development until adulthood.

Thus, from an informational view a great distinction exists between the Watson-Crick and epigenetic systems of heredity. In unicellulars, the  mother cell produces two copies of itself, physically passing on to each daughter cell a complete genetic information, the genome and the extragenomic genetic and epigenetic factors. Metazoans, in distinction, do not provide the offspring with the full amount of epigenetic information necessary for the individual development. Their contribute to the offspring is by far more modest: metazoans only communicate to the zygote (egg cell in parthenogenetic organisms) epigenetic information for advancing to a stage of development when the embryo becomes informationally self-reliable, a stage that coincides with the formation of the Bauplan at the phylotypic stage, including  the development of the incipient nervous system, rather than physically pass on to the offspring the full amount of the information for the final adult structure. In order to emphasize the distinction from the replicative heredity, i.e. the fact that in metazoans parents do not physically transmit to the offspring the full amount information for erecting their structure, I will tentatively designate this communicative heredity.

This mechanism of the communicative heredity is reminiscent of the von Neumann machine that, when provided with the necessary parts, could reproduce itself by appropriately assembling these parts and then providing them with a tape containing operating instructions. But being incomparably more sophisticated than the von Neumann’s machine, all the “zoomachines”, including us human beings, are different in some essential ways:

1. In clear distinction from the von Neumann’s machine, “zoomachines” are able to reproduce themselves not from parts (cells, tissues, or organs) but from chemical “scratch” of molecular elements.

2. While the von Neumann’s machine is assembled from the “parental von Neumann machine”, the “zoomachine” is self-assembled.

3. While the von Neumann’s machine” operates on instructions provided by the parental machine, the “zoomachine” computationally generates itself all the instructions (epigenetic information) for its function.

4. In distinction from the von Neumann’s machine, which would be operative only after being completely assembled, the “zoomachine” is operative before being completely assembled, while being self-assembled.

Like the parental epigenetic information provided with gametes, which controls the  pre-phylotypic development, the embryonically derived information that controls the post-phylotypic development is epigenetic in origin. That information is generated in the embryonic CNS in the form of electrical/chemical outputs resulting from the processing in neural circuits of enormous input of the stimuli from the developing embryonic structure and its environment. The computational activity of the central nervous system is essential for the  epigenetic system of heredity.

As an evolutionary innovation, the epigenetic system of heredity in metazoans represents a groundbreaking event in the evolution of life on Earth, whose importance in the evolution of life cannot be overestimated. It removed the principal obstacle in the way of the evolution of the metazoan form of life.

Essential in the evolution of the bigenerational epigenetic system of heredity in metazoans was the acquisition of the ability to produce self-developing unicellular structures, gametes/zygotes. As mentioned earlier, metazoans do not physically pass on the whole amount of the epigenetic information, but via gametes, they communicate to the offspring part of that information in the form of parental cytoplasmic factors (mRNAs, proteins, hormones, growth factors, neurotransmitters, nutrients, etc.) and imprinted genes. Under the influence of internal and external stimuli, by their own action and by activating specific zygotic genes, the parental epigenetic information deposited in the zygote controls and regulates the early development of metazoans up to formation of the Bauplan of the phylum and the species-specific operational CNS at the phylotypic stage. From this point in time on, the developing embryonic CNS is capable of determining cell differentiation, cell proliferation and the related processes of organogenesis and individual development in general. The postphylotypic metazoan embryo is informationally a self-reliable structure that selforganizes into an adult metazoan structure.

It is the parentally determined incipient CNS that, while developing, stepwise generates the huge amount of information necessary for the post-phylotypic development, for regulating the differentiation and proliferation of cells as well as for assembling billions/trillions of differentiated cells in that highly specific spatial arrangement that, in our visual perception, effectuates the animal morphology.

The epigenetic system of heredity is neither an extension nor a development of the Watson-Crick system. It is essentially product of an informational revolution and represents a qualitatively new property of metazoan life. The Watson-Crick system and the epigenetic system of heredity are evolutionarily as discontinuous as the genetic code and computational generation of epigenetic information are.

The epigenetic system of heredity is different from the Watson-Crick system of heredity with respect to the source, nature, and function of information it provides.

The genetic information is inseparable from the structure of DNA, the carrier of genetic information. In the process of its phenotypic expression (transcription and translation) a strict correspondence is established between the structure of the carrier of information, the gene, and the phenotypic product of its expression (RNA or protein). The structural order (primary structure) the genetic information induces in the resulting protein reflects the order of nitrogen bases in the nucleic acid structure. No similar correspondence exists between the structure of a neural circuit or its output (epigenetic information) and the order it determines in the target tissue or organ..

In contrast with the genetic code, which is believed to have been result of a “frozen accident”, the epigenetic information generated in neural circuits is adaptation-oriented and highly flexible. While a particular DNA segment codes for a strictly determined amino acid sequence, in the CNS, the same operational neural unit, the same circuit, depending on the stimulus and on its computational properties, may adaptively induce a number of different phenotypic results.

The computational processing of external stimuli and processing-dependent adaptive generation of the epigenetic information in neural circuits added a novel dimension to the relationship between the living systems and their environment. It enabled metazoans to virtually relate any external/internal stimulus to any gene, as it is manifested in numerous facts of expression of the same gene in response to different stimuli and the same stimulus inducing expression of different genes in the CNS of different species.

In the Watson-Crick system, in the process of the mitotic division, parents pass on to the daughter cells not only the total amount of genetic information in the form of DNA, the genome, but also the matter and energy necessary for their independent life. Both daughter cells are qualitatively finished cells. The daughter cells may grow but they do not go through a developmental process; they are born “developed”, in the meaning that from the beginning they are morphologically and functionally full-fledged individual organisms. The physical continuity of the Watson-Crick  system from the parent to the offspring is in contrast with the physical discontinuity of the parental and embryonic CNS in metazoans; metazoans do not transmit to the offspring the full amount of information necessary for developing species-specific structure. What instead metazoans pass on to the offspring via gametes is epigenetic information in the form of parental cytoplasmic factors and imprinted genes that regulate the formation of the zygote, the cleavage, and the early embryonic development. The parentally provided epigenetic information is consumed during the early development and has no role in the postphylotypic development, histogenesis, organogenesis and development of species-specific adult morphology.

The huge amount of information for the postphylotypic development of metazoan supracellular structure is generated in the embryonic CNS. It is the CNS that in the process of the post-phylotypic development, in response to the input of information on the developing embryonic structure throughout the animal body, and the external stimuli, computationally, stage-wise, generates the information necessary for the individual development until adulthood. In this meaning, the notion that in the process of their reproduction metazoans, like unicellulars, “produce copies of themselves” is inaccurate and misleading. In distinction from unicellulars, metazoans produce self-organizing, information-generating structures rather than “copies of themselves”.

Essential differences between the Watson-Crick and epigenetic systems of heredity exist not only as far as the nature and the mode of transmission of information is concerned, but also in relation to the mechanisms of generation of new information. In the Watson-Crick system, new information emerges by random changes occuring in the structure of the gene (DNA in general), as a result of thermodynamic factors. If mutations in the DNA structure happen to increase the fitness of the carrier in its environment, which is a very rare occurrence, they will be favored, saved and propagated in the offspring as new information, otherwise they will be discarded in the process of  elimination of their carriers under the action of natural selection.

In distinction, the new epigenetic information results from changes in the computational properties of circuits. These changes are not random but adaptive changes resulting from the adaptation-oriented processing of the input on external/internal stimuli in neural circuits. Similarly to the Watson-Crick system, whether the new epigenetic information will be sustained, propagated, or lost in future generations depends on natural selection.

The new genetic information arises randomly, and probably accidentally, whereas the new epigenetic information is computationally generated as an adaptive response of the organism for buffering noxious effects of external (and internal) agents or conditions.

During the template replicative Watson-Crick heredity the number of offspring a unicellular can produce per mitotic generation is strictly limited; it can produce only one copy (two daughter cells) in its lifetime. In communicative heredity, the possibility exists for the metazoan organism to produce more than one (depending on species from one to thousands) offspring during its lifetime.

As already mentioned, despite the essential differences between the two systems of heredity, the evolution of the epigenetic system of heredity does not mark the end of the Watson-Crick system of heredity in metazoans. The Watson-Crick system is still necessary and responsible for the heredity and reproduction at the cell and molecular level, for the biochemical evolution of metazoans in general. Hence, it is conserved in metazoans as a system that is complementary to the epigenetic system of heredity.

As for the relationship between the two systems in metazoans, the epigenetic system of heredity comprises and is inseparable from the genetic, Watson-Crick system of heredity. Both the genetic and epigenetic systems of heredity are present and operational at the cellular and supracellular levels respectively. They are functionally complementary and their mutual relationship has found a vivid expression in Medawars’ aphorism: “Genetics proposes, epigenetics disposes”. This is unambiguously manifested in the fact that, in metazoans all the signal cascades leading to expression/suppression of nonhousekeeping genes, and signals for cell reproduction and differentiation start with generation of electrical/chemical signals (=epigenetic information) in the CNS, or chemical signals released by local nerves. Thus, while complementary to the epigenetic system, the Watson-Crick system of heredity is subordinate to it.

The study of the epigenetic system of heredity and the epigenetic information, an almost terra incognita so far, could provide new insights into the nature of metazoan evolution and enable us to understand many of the unexplained biological phenomena, including the mechanisms of their evolutionary adaptation.