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NEURAL TISSUE
     The human nervous system is the most complex structure in the known universe.  No other object, whether seen through a telescope or microscope, approaches its complexity.  As difficult as it is to imagine, this incredibly complex structure is made up and run by cells, such as those pictured below.  These cells, particularly the neurons, utilize a host of proteins for their unique function in the human nervous system such as the proteins which allow them to generate electrical potentials, respond to neurotransmitters, and produce neuropeptides.  The gene families that include these proteins are not unique to the nervous system, nor are they unique to humans.  NEURONS

     The nervous system might have originated in primitive sensory cells which could stimulate local muscle contraction.  The ancestral neurons might have been simpler neurosecretory cells which would develop the ability to conduct impulses later their evolution.    Given that gut and pituitary hormones can be made in the brain and that neuropeptides can be made outside the nervous system, there is reason to believe that the nervous and endocrine systems are evolutionarily linked (LeRoith, 1981).

         In the nervous and endocrine systems, a variety of signals must be sent between cells.  A number of the signaling molecules found in the nervous and endocrine systems are known in organisms which lack these systems.  Bacteria such as E. coli synthesize a protein similar to insulin and several protozoans are known to make peptides similar to adrenocorticotropic hormone, β-endorphin, and dynorphin (LeRoith, 1981).  Ciliates can possess receptors for substances which effect neurons such as ACh, neurepinephrine, and epinephrine.  A mating pheromone in the protozoan Blepharisma resembles serotonin.  The use of cAMP in signal transduction is involved in processes other than neural function and cAMP can even serve as an extracellular signal in slime molds (Mackie, 1990).  Some plants use the signaling molecules glycine, GABA, glutamate, and ACh (Mackie, 1990).  The simple nervous system of cnidarians includes the use of neuropeptides (Mackie, 1990).

     In essence, the nervous system runs on electricity.  Thought is electrical.   Remembering your grandmother, preferring one outfit over another based on your favorite color, and recognizing the voice of your best friend all require that neurons conduct electricity.  The ability of neurons to conduct electrical messages (action potentials) along their axons depends on their ability to generate resting electrical potentials across their cell membranes.  This is a characteristic of most cells in the human body and many unicellular organisms as well.  Some ciliates, such as Paramecium and Opalina, generate negative resting membrane potentials which, when stimulated, produce an influx of calcium which results in a reversal of the ciliary beat.  Membrane depolarization results in the luminescent response in the dinoflagellate Noctiluca.  Action potentials are known in the alga Nitella, the sensitive plant Mimosa and the venus flytrap (Prosser, 1973, p. 457).  Yeast possess a number of genes which direct vesicle movement and CAM kinase II (which is essential for the formation of long term memory in vertebrates) (Mineta, 2003). 

      Although the ability to conduct electricity is most commonly identified with the nervous and muscular systems, other cell types can carry electrical messages as well.  This more primitive transport of electrical messages may provide insight into the evolution of nervous tissue.  The epithelia of ctenophores and jellyfish can conduct electrical messages without neurons.  This neuroid conduction is known in epithelial and muscle sheets of higher animals as well (Hoar, 1983, p. 133-4).  Electrical coupling is known to occur between the embryonic cells of squid, starfish, fish, and tadpoles.  For example, in tadpole embryos, action potentials travel through the skin before nerves develop.  Intercellular junctions (such as gap junctions) allow electrical coupling between cells in fly salivary glands, toad bladders, mouse livers, and malphigian tubes (Prosser, 1973, p. 461-2).  Gap junctions allow electrical flow through cardiac and smooth muscle.  Many neurons are linked by electrical synapses and these synapses are known between neurons in worms, mollusks, and arthropods and in vertebrates from fish through mammals. (Prosser, 1973, p. 483).

     The following images are of multipolar mammalian neurons.

NEURON NEURON
NEURON NEURON
NEURON  

      Cnidarians possess two types of nervous cell: sensory and deeper ganglion cells.  Ganglion cells synapse with each other and with muscle cells.  The neurosensory cells seem to be the more primitive of the two since they are less differentiated (they lack dendrites, for example) and they are very abundant in lower vertebrates.  Examples of neurosensory cells in higher animals include the receptor cells of parietal and lateral eyes (including rods and cones), infundibular cells in fish, and olfactory neurons.   In humans, only the receptor cells of the olfactory epithelium and retina are of this type.

     In cnidarians, ganglion cells possess both Nissl substance and dendrites.  These neurons are considered as primitive since they lack myelin and impulses are transmitted slowly.  Only in bilateran animals do neurons transmit impulses in only one direction and possess both dendrites and axons (Ariens).    Autorhythmic behavior of neurons in which neurons can initiate action potentials on their own is known in both vertebrates and invertebrates. (Hoar, 1983, p. 305).      

     Flatworms are the most primitive bilateran animals and their nervous systems possess a number of features known in higher animals.  Unipolar, bipolar, and multipolar neurons are known in the most primitive flatworms, the acoels (Rieger, from Harrison, 1991).  Higher flatworms possess multipolar neurons with dendritic spines and soma exterior to axons, electrical synapses, tetrodotoxin sensitive sodium channels, voltage-gated fast sodium channels, dark adaptation of the eye, habituation, cells similar to hypothalamic neurosecretory cells, and the use of NE, E, serotonin, ACh,  and neuropeptides in signaling (Sarnat, 1985)  Nitric oxide and nitric oxide synthase are known in flatworms and higher animals but not in cnidarians (Tandon, 2001).

     One type of neuron has apparently evolved only recently in the human lineage.  The spindle cells of the anterior cingulate gyrus of the brain (layer Vb) is known to exist only in higher primates.  These neurons only form clusters in humans and chimps.  They are involved in the control of meaningful vocalizations in New World and Old World monkeys.  Lesions in the area which contains these clusters in humans can result in mutism.   Since this type of neuron suffers greatly in the neurodegeneration of Alzheimers, it is hypothesized that the relative newness of this type of cell is related to its susceptibility to disease (Nimchinsky, 1999).

 

THE GENES WHICH CAUSE THE DEVELOPMENT OF NEURONS

     What genes allow cells to differentiate into neurons?    What genes guide the early development of the nervous system?  There are many, only a few of which are given here.  It turns out that many of the genes which are essential for the development of human neurons are not unique to neurons, nor are they unique to humans.  Many of these genes are members of gene families which evolved prior to the evolution of animals with nervous systems.

     Of 116 genes known to be involved in the development of the brain and nervous system of flatworms, more than 95% were shared with higher bilateran animals such as nematodes, flies, and humans.  Homologs of all 116 existed in humans.  Homologs of about a third of these genes existed in organisms which lack a nervous system, such as yeast (Mineta, 2003). 

     These shared genes include FGF, noggin, frizzled (a Wnt receptor), immunoglobulin/cadherin family members, otx, neuropeptide Y, NCAM, BMP receptors, and rhodopsin (Mineta, 2003).  Members of the Wnt gene family are involved in the formation of the vertebrate brain and also in the regeneration of planarian brain (Marshal, 2003).  apterous is a member of the LIM-homeodomain family which possesses 2 zinc finger-like domains in addition to its homeodomain.  Both apterous and mammalian homologs are expressed in nerve cords, eyes, brains, limbs, and olfactory structures.  The human gene can replace the activity of apterous in the body of the fly (Rincon-Limas, 1999).

     There is a new family of genes (C. elegans unc-76) known to affect axonal growth in nematodes and humans.  Mutations affect the formation of fascicles and nerve cords (Bloom, 1997).  Tunicates possess genes involved in the induction of neural tissue and for neural function which link them to vertebrates rather than protostomes (such as a greater diversity of Bmp and Wnt signals, the gene Nodal, SCO-spondin, noelin, and rhodopsin photoreceptors related to deep brain/pineal opsins of vertebrates) (Dehal, 2002).  Mutation of the nou-darake (Djndk) gene in planarians caused an ectopic brain to form in the trunk region (Mineta, 2003). 

    A unique group of important embryonic cells called neural crest cells were a vertebrate innovation.   Many of the characteristics which set vertebrates apart from more primitive chordates are determined by these neural crest cells.  Neural crest cells develop into a number of cell types including sensory neurons, adrenergic neurons, cholinergic neurons, Rohon-Beard cells, satellite cells, and glial cells.  As a result, the neural crest contributes to spinal ganglia, the sympathetic and parasympathetic divisions of the ANS, and brain, among other structures (Hall, 1999).  In tunicates, there is evidence of a protoneural crest in the pigmented cells along the neural tube (Hall, 1999).    Although there are no neural crest cells in tunicates, the expression of the snail gene family member, Hrsna, indicates that some of the characteristics of neural crest cells may be present. (Meinertzhagen, 2001).   While Amphioxus lacks neural crest cells, it expresses many of the important genes involved in the differentiation of vertebrate neural crest cells in the region of the junction between the neural plate and the non-neural ectoderm.  Thus, it appears that vertebrate neural crest cells employed genes which were already present in vertebrate ancestors (Ahlberg, 20-5).

      The genes required to form the neural crest did not appear suddenly in vertebrates.  Neural crest induction involves genes such as BMP, chordin, FGF, TGF (at Hensen’s node), WNT, Shh, dorsalin, odd-paired (a Drosophila pair rule gene), and the snail zinc finger gene.  Many of these genes perform other functions as well and are known (or, at least, members of their gene families are known), in more primitive animals which lack neural crest cells. 

       As brains became more complex, additional proteins were recruited to achieve this complexity.  A significant feature of the mammalian cerebrum is its organization into layers.  The protein reelin is involved in a number of neural functions in amniotes such as neuronal migration to form layered regions of the cerebral cortex, synapse formation in the hippocampus, and axonal growth.  Reelin is also expressed throughout the lamprey brain (Perez-Costas, 2002).  Although there have been observations of molecular differences between human and chimp brains, many correspond to varying level of a protein’s expression rather than the existence of new proteins.  There are a large number of genes which are more highly expressed in the brains of humans than those of other primates (Caceres, 2003).   The G72 gene is unusual in its rapid evolution in related primates such as humans and chimpanzees.  It is involved in the regulation of NMDA receptors, which are involved in learning and even implicated in schizophrenia (Chumakov, 2002).

      Sialic acids are important in deuterostomes.  Most mammals, including all of the great apes, possess the sugar N-acetylneuraminic acid (a sialic acid) at the ends of glycoproteins, both soluble and those of the cell membrane.  Humans lack this sugar because of a mutation in the human CMP-N-acetylneuraminc acid hydroxylase gene.  The human gene CMP-N-acetylneuraminc acid hydroxylase possesses a deletion which caused a frameshift mutation in the gene, rendering it a pseudogene.  It is unknown what effects this mutation had on human evolution, if any, but it may be relevant that brain tissues of non-humans typically express low levels of sialic acid, even when levels in the rest of the body are high.  If sialic acid expression is in some way a detriment to neural functioning, it may be that the loss of its expression had an impact on hominid brains.  Two neanderthal fossils have also been shown to lack this sugar (Chou, 1998; Chou, 2002).

     In mice, there is a gene which codes for an RNA molecule which is not translated into protein and is expressed only in the nervous system.  It is not known in any other group of mammals.  It arose when a tRNA gene for alanine was integrated into a new site (Kuryshev, 2001).  In the genomes of anthropoid primates, a small non-messenger RNA is expressed in the brain (Kuryshev, 2001).

 

THE GENES NECESSARY FOR NEURON FUNCTION

     A neuron’s ability to create resting and action potentials rests in its ability to transport ions, particularly potassium and sodium ions.  Potassium channels are ancient proteins which evolved in organisms long before the ability to transmit electrical messages.  Prokaryotes (eubacteria and archea) are known to possess potassium channels and these channels are homologous to those found in eukaryotes (Jiang, 2002). Eukaryotic channels retain their function when the eukaryotic channel pore is replaced by the pore from prokaryotic channels (Lu, 2001).  As pictured below, the potassium channel is not only the simplest of the voltage regulated ion channels, its 6-transmembrane region structure (with the fourth unit being the voltage-regulated portion) is the prototype for the more complex sodium and calcium channels which are composed of four separate homologous regions.  The simplest potassium channels form tetramers using four subunits of the same gene. (Darnell; Yellen, 2002).The potassium, sodium, and calcium voltage regulated channels are pictured below (after Darnell, p.782).

 

POTASSIUM CHANNEL SODIUM AND CALCIUM CHANNEL

The ion channels for potassium, sodium, and calcium belong to the same ion channel family (along with cyclic nucleotide-gated channels and several others).  Variations in potassium channel receptors can cause heart rhythm abnormalities, hearing loss, and seizures.

     While eukaryotic sodium channels are large proteins, composed of four homologous domains of a potassium-channel like region, a simpler sodium channel is known in bacteria.  It has a single domain, homologous to potassium channels (Catterall, 2001).  In vertebrates, voltage regulated sodium channels share a common structure and are not only expressed in excitable cells (neurons and muscle) but some nonexcitable cells as well (such as astrocytes and Schwann cells). 

While invertebrates only have one or two genes for voltage-dependent sodium channels in their genomes, mammals possess ten.  As with other gene families (such as the globins and the Hox genes), it appears that genome duplications at the base of the vertebrate lineage and more recent tandem duplications of individual genes are responsible for this expansion.  In the human genome, the genes for voltage-dependent sodium channels are located on four chromosomes with clusters of five tandem genes on chromosome 2 and three tandem genes on chromosome 3 (Lopreato, 2001).

Variations in sodium channel receptors can cause epileptic and other types of seizures, heart arrhythmias, hypertension, and disorders affecting movement.

 

G PROTEIN COUPLED RECEPTORS

    Neurons must be able to respond to a wide variety of neurotransmitters, neuropeptides, hormones, light, olfactory stimuli, taste stimuli, and other stimuli.  Interestingly, most of these phenomena are perceived by the use of the members of one gene family, the G-protein coupled receptors.  G-protein coupled receptors are used in many cell types other than those of the nervous system and evolved very early in the history of life, long before the evolution of animals.  This superfamily of proteins share a set of 7 hydrophobic transmembrane regions connected by hydrophilic sections which form either intracellular or extracellular loops.  This is a very old family found even in bacteria; bacteriorhodopsin is homologous to GPCRs of higher organisms although exon shuffling has changed the order of the transmembrane regions.  Gene duplication had produced many of the subfamilies of the G proteins (Suga, 1999). 

     This family of receptors is actually the largest gene family known in vertebrate genomes (including that of humans).  These receptors mediate the activity of most neurotransmitters and neuropeptides in addition to serving as receptors in the cells which perceive taste, smell, and sight.  The use of these chemical messages and the G protein coupled receptors which perceive evolved long before the complex nervous systems of higher vertebrates.  Serotonin, enkelphans, and endorphins are known in flatworms (Rieger, from Harrison, 1991).  Echinoderm genomes include the GPCR receptors for oxytocin, endothelin/bombesin.neuromedin, CCK/gastrin, orexin, TRH, tachykinin, galanin, RFamide, prolactin-releasing hormone, and gonadotropin (Burke, 2006). Echinoderms possess a number of the enzymes involved in neurotransmitter production shared by vertebrates. These include enzymes involved in the metabolism of serotonin (tryptophan hydroxylase, AADC), dopamine (monamine oxidase, COMT), NO (nitric oxide synthase), noradrenaline, GABA, histamine, and Ach (Burke, 2006). Although noradrenaline is known in echinoderms, adrenaline may be limited to vertebrates (Burke, 2006).Hemichordates, for example, utilize ACh and  NE as neurontransmitters  (Benito, form Harrison 1997, p. 98) and jawless fish add GABA is an inhibitory neurotransmitter and glutamate as an excitory neurotransmitter (Hardisty, p. 328).  

     Both neuropeptides and their receptors have been conserved through evolution.  Neuropeptides serve as neuromodulators in vertebrate and invertebrate nervous systems and can function as neurotransmitters in invertebrates.  In C. elegans, about 130 putative receptors for neuropeptides have been identified.  Some of the neuropeptides involved have not yet been found in vertebrates.  In mammals neuropeptides function in a variety of neural pathways, including those involving feeding and sleep. There are more than 60 neuropeptides in the mammalian brain; most of them act through G-protein coupled receptors (Nathoo, 2001).

     G protein coupled receptors are the receptors for all of the following signaling molecules in the nervous system.

 

DOPAMINE

     The neurotransmitter dopamine is involved in the perception and pursuit of pleasure.  It is involved in almost every type of addiction and dopamine treatment can decrease addiction.  Its release increases sex drive and is a factor in orgasm.   There are several dopamine receptors in the human genome whose variations (including those of DRD4, one of the most variable human genes known) have been shown to be a factor in schizophrenia, recurrent major depression,  adolescent emotional disorders, alcoholism, Parkinson-like disorders,  scores on personality tests related to  novelty seeking.

 

EPINEPHRINE

     Epinephrine is not only a neurotransmitter, but it also functions as a hormone when released from the adrenal glands during the fight or flight response.  Amphetamines resemble NE.  Variations in epinephrine receptor genes may affect blood pressure,  in basal metabolic rate, obesity, and susceptibility to congestive heart failure.

GABA (gamma amino butyric acid)

     GABA is the major inhibitory neurotransmitter of the vertebrate brain.  More than a dozen genes code for the subunits which can be combined to form the receptor protein.  One cluster on chromosome 15 possesses the GABAR genes B3—A5—G3 and duplications of this cluster seem to have given rise to the cluster on 5q34 containing the genes B2—A6—A1—G2 and the cluster on 4p12 containing the genes B1—A4—A2—G1.  Variations in GABA receptor genes have been linked to epilepsy, bipolar disorder, insomnia, autism, and febrile seizures.

 

GLUTAMATE

Glutamate is the major excitory neurotransmitter in the mammalian brain.  Many glutamate receptors function in learning.  The glutamate receptors expressed in insect muscle are the functional equivalents to nicotinic acetylcholine receptors in vertebrates (Schuster, 1991).

 

OPIOID FAMILY

     Opioids are signals which function in pain stimuli, feeding, sexual behavior, learning, thermoregulation, development, and the physiology of the cardiovascular and respiratory systems.  The opioid met-enkalphin promotes cell proliferation in several bacteria and protists which possess opioid receptors (Zagon, 1992; Danielson, 1999).  Opioid-like peptides known from arthropods, mollusks, and annelids.  Pordynorphin and large peptide precursors of opiates seem to exist in mollusks (Stefano, 1998; Darlison, 1997).

     Enkalphin and POMC are known in several non-amniotes, including aganthans.  The duplication of the ancestral gene preceded craniates.  Proorphanin seems to have resulted from an early duplication of the gene for proenkalphin in gnathostomes.  Another duplication of the proenkalphin gene produced prodynorphin in the lineage which produced sarcopterygians and tetrapods (Danielson, 1999).  The skin of amphibians can possess a number of opioids which act on μ and δ opioid receptors (Schmidt, 1997).

SALAMANDER

SEROTONIN

The neurotransmitter serotonin inhibits sex drive and orgasm; promotes contentment, causes cravings for sweets and has been used to treat depression, obsessive-compulsive disorder, panic, anxiety, PMS.   Receptors for serotonin are involved in the regulation of sleep, appetite, thermoregulation, pain, and sexual drives. 

TRACE AMINES

While invertebrate nervous systems use biogenic amines such as tyramine, b-phenylethylamine, tryptamine, and octopamine as neurotransmitters, their role is not yet clear in vertebrate nervous systems.    In vertebrates, the effects of the biogenic amines norepinephrine, dopamine, and serotonin are mediated through G-protein coupled receptors.  Mammalian nervous systems possess GPCRs which interact with these trace amines as well whose receptors belong to a family of GPCRs (TA1 through TA15) whose function is not well understood (Borowsky, 2001).

 

NEUROPEPTIDES

     In addition to a variety of neurotransmitters, nervous systems utilize a variety of neuropeptides.    The human nervous system uses many of the same neuropeptides found in the nervous systes of invertebrates.  Cnidarians  produce FMRFamide-like peptide, oxytocin/vasopressin, and other peptides (Thorndyke, ).  Cells of a sea anemome are depicted below.

CNIDARIAN
     FMRF and somatostatin, are known in flatworms (Rieger, from Harrison, 1991).  A large number of peptide signals had evolved prior to the division of the coelomate lineages.   Evidence indicates that mollusks (such as the slug in the following image) synthesize vasopressin, vasotocin, oxytocin, CRF, ACTH, αMSH, enkephalin, dynorphin, somatostatin, substance P, glucagons, insulin, secretin, gastrin, calcitonin, VIP, GIP, PP, FMRRamide, AKH, dopamine, serotonin, histamine, and octopamine (Thorndyke, ).  
SLUG

     Protochordates synthesize bombesin, calcitonin, β endorphin, enkephalin, gastrin/CCK, glucagons, insulin, LHRH, motilin, αMSH, neurotensin, PP, prolactin, secretin, somatostatin, substance P, VIP, serotonin (Thorndyke, ).  Tunicates possess genes for all major peptide hormone receptors (such as insulin and gonadotropins), except growth hormone (Dehal, 2002).   

     To date, GnRH (two forms), somatostatin, neuropeptide Y, and tachykinin are known to be produced in the lamprey brain.  GH, ACTH, MSH-A, MSH-B, NHF (nasohypophysial factor), and AVT (arginine vasotocin) are synthesized in the lamprey in the pituitary (Sower, 2001).

     Somatostatin is expressed in the central nervous system, pancreas, intestine, and stomach where it functions as a hormone or neuromodulator.  The amino acid sequence is identical from jawless fish through mammals.  A second somatostatin gene (termed cortistatin in mammals) is known in actinopterygians, sarcopterygians, amphibians, and mammals (Trabucchi, 1999).

      Neuropeptide Y (NPY), gut endocrine peptide YY (PYY), pancreatic polypeptide PP (PP) and pancreatic polypeptide PY (PY) are all composed of 36 amino acids (except in chicken PYY which possesses 37).  NPY-like neuropeptides have been found in flatworms (such as the planarian in the following image), mollusks, and tapeworms (Larhammar, 1993; Hoyle, 1998). 

Annelid worms synthesize dynorphin, and enkelpalin-like substances.  Insects synthesize oxytocin, vasotocin, vasopressin, neurophysin, substance P, bombesin, gastrin/CCK, VIP, PP, serotonin, and dopamine (Thorndyke, ).
INSECT
PLANARIAN

NPY had evolved by the appearance of jawless fish and a duplication of the NPY ancestral gene occurred before lampreys to produce NPY and PYY.  Pancreatic polypeptide arose from a gene duplication of the ancestral PYY (peptide YY) gene only in tetrapods.  A duplication in some teleosts produced the neuropeptide PY.  (Youson, 1999; Larhammar, 1993). 

     All vertebrates possess neuropeptide Y in central and peripheral nervous systems (Larhammar, 1993).  The distribution of neuropeptide Y recognition sites in the brains of lungfish is similar to that observed in amphibians (Vallarino, 1998).  Mutations in the NPY gene cause the obesity in mice and is involved in the control of lipid metabolism.  In humans, polymorphisms of this gene have been correlated to variations in serum cholesterol, LDL levels, atherosclerosis, and serum triglyceride levels.  NPY also has other roles: it is expressed in the olfactory epithelium and, in mice, affects alcohol intake.  One polymorphism in humans is observed more frequently in those who are alcohol dependent (OMIM).

 

OXYTOCIN/VASOPRESSIN FAMILIES

     Oxytocin is the signal which induces labor in placental mammals, milk release in mammals, and is a major factor in orgasm.  Oxytocin (and the very similar signaling molecules of vasopressin, mesotocin, conopressin, etc.) evolved in more primitive animals. Most metazoan animals use sex steroids in differentiation of male and female reproductive structures and oxytocin for the majority of the acute events that occur at these structures structures.  Oxytocin and vasopressin family members are known from 4 invertebrate phyla and all groups of vertebrates (Youson, 1999).  Cnidarians produce oxytocin/vasopressin (Thorndyke, ).  A number of peptides similar to oxytocin/vasotocin are known in invertebrates such as Arg-conopressin-S in mollusks, Lys-conopressin-G in mollusks, cephalotocin in mollusks, annetocin in annelids, Lom-DH in arthropods, and Stp-OLP in tunicates.  Mollusk conopressin genes are homologous to those of vasoticn/oxytocin in vertebrtates (Hoyle, 1998; Youson, 1999; Kesteren, 1992).    In worms, annetocin functions in egg-laying and the contraction of neprhidia (which propel both wastes and gametes) (Ivell, 1999).

    The neurohypophysial hormones of vertebrates are divided into two groups: oxytocin and vasotocin families.  Lungfish have the same oxytocin family member, mesotocin, found in amphibians, reptiles, and birds as opposed to the isotocin found in teleost fish (such as the teleost hatchling pictured below).  The vasotocin family member in lungfish, copeptin, has two regions which are shared with amphibians rather than with teleost fish (Hyodo, 1997).

FISH
.  Oxytocin functions in a paracrine hormone in mammals, being produced in the hypothalamus, pituitutary, mammary gland, ovary, uterus, testis, and prostate.  Oxytocin functions as an endocrine hormone initiating the events of childbirth and milk ejection.  In ruminant mammals, oxytocin is secreted from the ovary to induce luteolysis and in induces the formation of the corpus luteum in marmosets.  The processes regulated by oxytocin tend to be positive feedback mechanisms (such as in birth, milk ejection mediated by neurons followed by recovery, and in the deterioration of the corpus luteum, (Ivell, 1999). The cells of the posterior pituitary (which secrete oxytocin) are depicted in the following image.
PITUITARY

     The single amino acid mutation in ancestral vasotocin which gave rise to vasopressin seems to have occurred only in the ancestral mammals.  All non-mammalian vertebrates possess vasotocin (Hoyle, 1998).

 

TACHYKININ FAMILY

     The human nervous system depends on additional signals which evolved in more primitive organisms.  Substance P, tachykinins, and neurokinins are members of a gene family.  No known invertebrate peptides are known which belong to this family (Hoyle, 1998).

      Neurokinin A is known in all tetrapods. (Hoyle, 1998).  Frogs possess additional kinin molecules. Substance P is related to kinins and is known in amphibians and sharks (Hoyle, 1998).  Mammals are known to possess several members of a tachykinin family including substance P, neuromedin K and neuromedin L.  Other tachykinins are known in amphibians (Kozawa, 1991). 

GLIA

    While most of the study of the nervous system typically concentrates on the function of neurons, there is a second type of cell in the nervous system known as neuroglia.  Glial cells actually outnumber neurons and perform a variety of functions such as the creation of the blood-brain barrier, the phagocytosis of microbes, the creation of currents for cerebrospinal fluid, and the production of myelin sheaths around neuronal axons. 

     There are several genetic components involved in the differentiation of multipotent precursor cells into either neurons or glia which are conserved between flies and vertebrates such as glide/gcm, Notch, and the involvement of Helix-Loop-Helix transcription factors.  Mammalian gcma can substitute for Drosophila glide and the fly gene can induce glial cell differentiation in vertebrate neural cell lines (Van de Bor, 2002; Kim, 1998).  Sonic Hedgehog and Bmp proteins can induce cerebellar granule cell precursors to differentiate into astroglia (Okano-Uchida, 2004).

     Some hydra neurons are wrapped in sheaths similar to glia (Mackie, 1990). Glia similar to astrocytes exist in planarians (Sarnat, 1985) and some neurons are wrapped in a glial sheath (Rieger, from Harrison, 1991).  In nemertines, there are glia-like cells associated with nerves and near the gut. ( Harrison, 1991).  In Drosophila, some neuroblasts develop only into glial cells, others develop only into neurons, while others develop into a mix of both (Bossing, 1996).

No myelin is yet known in hemichordates (Benito, form Harrison 1997, p. 98).  Myelin sheaths are known in arthropods but they differ from those found in vertebrates (Ariens).  In both vertebrates and invertebrates, Schwann cells may wrap many naked axons together.  Saltatory conduction has only been demonstrated in vertebrates. (Hoar, 1983, p. 144). 

     Tunicates possess glia-like cells which support neurons. (Ruppert, from Harrison, 1997, p. 470).  Of the roughly 330 cells of the tunicate brain, 70% are glial cells (Nieuwenhuys, 2002).   Like other lower chordates, there is no myelin.  Ciliated ependymal cells exist along the neural canal, as in vertebrates (Meinertzhagen, 2001).  Lancelets have at least two types of glia: astocytes and ependymal cells.  Some glial cells express Pit-1 which is a POU domain protein expressed in the pitutary to regulate growth hormone and prolactin in vertebrates.  The glial cells which express this may be homologous to the ependymal tanycytes in mammals (Candiani, 1999).

Although modern jawless fish may possess axons surrounded by glial cells (a condition also known in higher vertebrates), there is no evidence of myelin in modern lamprey and hagfish (Bullock, 1984).In gnathostomes, oligodendrocytes and astrocytes exist and the nervous system is myelinated. (Hoar,VOl. IV, 1970, p. 8).  The major proteins of myelin evolved early in the vertebrate lineage, given their presence in fish (Vourc’h, 2004).  Ependymal cells in teleosts retain the ability to become neurons (Hoar,VOl. IV, 1970, p. 9).  The percentage of cerebroside hydroxy fatty acids in the brain lipids of coelocanths is similar to tetrapods and unlike other fish (including lungfish) (Tamai, 1994).  Astroglia with long processes are primarily known only in primates.  In bats and insectivores, they exist but are limited to the ventral basal cortex.  They can be present or absent in prosimians and New World monkeys (Colombo, 2000).