Common patterns of neuroendocrine integration in vertebrates and invertebrates

GENERAL AND COMPARATIVE

Common

ENDOCRINOLOGY

61, 452-458

(1986)

Patterns of Neuroendocrine Integration and Invertebrates

in Vertebrates

Comparison between neuroendocrine integrations in vertebrates and invertebrates at the molecular (gene structure, precursor processing) and cellular (cell-cell hierarchy) levels. reveals common patterns. “Secondor third-order” hormonal cascades starting with a brain neurohormonal signal. are amplified and directed by one or two glandular relays. A parallelism may be found between the induced neurohormonal controls of reproduction. A neuroendocrine program involving several peptides could be recorded within a single gene. n 1986 Academic Pre\\. Inc.

When Jean-Baptiste-Pierre-Antoine de Monet, Chevalier de Lamarck was appointed, in 1793 by the Convention, at the chair of the Animals without vertebrae in the new “Museum d’Histoire Naturelle” he proposed, in his first course, a partition of the animal kingdom into vertebrates and invertebrates, instead of the Linnaeus’ classification in three “degrees” (warm blood, cold blood, and pseudoblood), itself derived from that in two classes (with or without blood) used by Aristotle (1). About two centuries later, molecular biology divides the living species into prokaryotes and eukaryotes and the distinction between vertebrates and invertebrates seems of minor importance for biochemists. In the last S years many biologically active peptides found in vertebrates have been identified in invertebrates and conversely (2, 3). It remains, however, to bring out the common patterns of the physiological integrations in these two groups. The first comparison between the neuroendocrine functions of invertebrates and vertebrates was probably made by Scharrer and Scharrer (4) when they pointed out “an interesting parallelism between the intercerebralis-cardiacum allatum system of insects and hypothalamo-hypophyseal

system of vertebrates.” The general idea was emerging that the neural control of the known endocrine glands must pass through regulatory neurohormones and therefore that a multistep neuroendocrine cascade should be implied not only in the cyclic physiological functions but also in the development . Nervous regulation and endocrine regulation are now regarded as tightly related and because both neurotransmitters and hormones are gene products, highly integrated functions such as innate behavior begin to be analyzed at the genomic level (5). THE MULTIPLE PEPTIDE PRECURSORS AND THEIR PROCESSING

It is generally admitted that in vertebrates and invertebrates the same peptides may fulfill both hormonal and transmitter functions, and consequently that the same structural genes may be expressed in both glandular and neural cells. The processing of the gene products, the precursor proteins, may, however, differ according to the cells since, for instance, the cholecystokinin (CCK) precursor is processed essentially into CCK-8 in neurons and mainly into CCK-33 in gut endocrine cells (6); in

NEUROENDOCRINE

INTEGRATIVE

causing contraction of the reproductive duct (10). Many bioactive peptides have an cyamidated residue at their carboxyl end. The precursor proteins to amidated peptides virtually always contain the amino acid sequence -X-Gly-LysiArg - LyslArgwhere X is the residue that becomes amidated in the mature peptide (9). Amidated a-MSH is released from the proopiomelanocortin in this way and y-MSH is believed to be amidated because of the presence of this sequence in the precursor. For the same reason it is assumed that the 36-residue ELH is amidated although direct proof has not yet been given with the isolated peptide (5). The cleaving-amidating enzymic system, which seems to involve a glycine dehydrogenase, is therefore apparently older than the vertebrate-invertebrate divergence. Another similarity between the vertcbrdte and invertebrate multihormoneitransmitter genes is the presence of nearly identical repetitive sequences within the genes and therefore within the precursors. in the proopiomelanocortin, (Y-, B-, and r-MSH have been identified and, in the ELH precursor, the p-, y-. and S-factors arc consecutive homologous pentapeptides separated by pairs of basic residues. Duplication of a short DNA sequence within the gene may have occurred during evolution. The possible cooperativity between the actions of peptides deriving from a single protein precursor is not easy to decipher because of the multiple functions of a given peptide and because of the complexity of the neuroendocrine integration. However.

the same way, proopiomelanocortin is split in the anterior pituitary into corticotropin (ACTH), B-lipotropin, p-endorphin, and a 18K N-terminal glycopeptide whereas corticotropin is cleaved further to cu-MSH and corticotropin-like intermediate lobe peptide (CLIP) and l3-lipotropin is cleaved to B-MSH and B-endorphin, in the intermediate pituitary (7). But whatever the processing, the precursor protein generates several peptides active either as a hormone or as a transmitter (Figs. I. 2). The first multihormone precursor genes to be identified were, in vertebrates, the bovine proopiomelanocortin gene (8) and, in invertebrates the three egg-laying hormone (ELH) precursor genes of the marine snail Aplysia (5). The sizes of the precursor proteins are similar (265 residues for proopiomelanocortin precursor, 271 residues for ELH precursor). The enzymes involved in the processing are similar since cleavages of the polypeptide chain occur virtually always at pairs of basic amino acids (lysine or arginine) (9). Both proopiomelanocortin and ELH precursors have 10 of these putative cleavage sites. Most of the predicted peptides have been isolated in the case of proopiomelanocortin; for the ELH precursor, four of the potential peptides are known to be released by two clusters of neurons, the bag cells. at the top of the abdominal ganglion: the p and (Y bag-cell factors, ELH and acidic peptide. The first three have been shown to act as neurotransmitters, altering the activity of specific abdominal-ganglion neurons (5). Furthermore ELH acts as a hormone, entering the circulation and

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453

PSYCHOLOGY

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FIG. 2. The three precursors encoding for the ELH, A, and B peptides in the sea-hare Ap[y.~;~ ca&~nica. Met indicates the N-terminal methionine. Arrows represent potential or known cleavages at dibasic, tribasic or tetrabasic residues. If COOH-terminal amidation is believed to occur, an NH2 appears above the arrow. The A/B peptide homology is represented by stippled boxes, the ELH homology by cross-hatched boxes, and the acidic peptide homology by parallel diagonal lines enclosed in boxes [from (S)].

in invertebrates such as Aplysia californica, the central nervous system is numerically simple, consisting of about 20,000 nerve cells instead of 101” neurons for the human brain and a cooperation, as neurotransmitters, between the peptides derived from ELH precursor in the bag-cells seems to exist. Three of these peptides have been shown to be active specifically on different neurons of the abdominal ganglion: the (Yfactor inhibits cells Lz, L,, L,, and L6, the p-factor excites cells L, and RI and ELH augments the firing of cell R 15. The association of these three individual peptides encoded by a single gene, correlated with the activity of different sets of neurons, suggest that a mechanism may be responsible for generating the complex array of behaviors associated with egg laying (5).

E. Scharrer (12) has formulated some general principles governing the relationships between the endocrine and nervous systems (Fig. 3): ” 1. The central nervous system receives and integrates information EXTEROCEPTIVE AND INTEROCEPTIVE STIMULI / \

A COMM0k.l HIERARCHY IN THE NEUROENDOCRINE INTEGRATION

The process of neural secretion can be resolved into essentially the same steps as those observable in the production of zymogen granules by the cells of the exocrine pancreas (11). Neurosecretory granules arising from the Golgi apparatus pass within the axons into terminals where they are temporarily stored. Neurosecretory nerve endings may become associated with blood vessels to form “neurohemal” organs. These include the neurohypophysis of vertebrates, the sinus gland of crustaceans, and the corpora cardiaca of insects.

FIG. 3. General diagram of neuroendocrine integration. The arrows symbolize both nervous and hormonal connections, In any given case of a function under neuroendocrine control in any particular animal only some of the pathways are actually used [from (1311.

NEUROENDOCRINE

INTEGRATIVE

and stimuli that affect endocrine functions. This input, in addition to hormonal feedback, originates in organs of special senses, i.e., chemoreceptors, photoreceptors, and acoustic apparatus or may be received from systems serving general visceral and somatic sensation such as touch, pain, and temperature. 2. The combined input must eventually reach a final common path which may be either nervous or hormonal. 3. The hormonal final common path acts either directly on effector organs or through endocrine glands that serve as amplifiers of signals from the central nervous system. 4. Hormonal and neural feedback from the target organs complete a neuroendocrine circuit.” These relationships should now be specified at the molecular level. A single combination of neural and endocrine pathways such as the milk ejection in nursing mammals, brought about by tactile stimulation by the suckling young through the release of oxytocin, which in turn stimulates myoepithelial cells in the mammary gland, has been designated as a “first-order” neuroendocrine system (12, 13). The neurohormone produced by the central nervous system may not act directly on an effector organ but activate an endocrine gland. which in turn stimulates the final target (“second-order system”) or another endocrine gland acting itself on the target organ (“third-order system”) so that a hormonal cascade may be required to transmit a brain signal (Fig. 4). The third-order systems are well known in mammals where hypothalamic liberins or statins act on adenohypophysial cells, which in turn, through tropins, stimulate the peripheric endocrine glands. In insects, two antagonist second-order systems are involved in molt and metamorphosis (ecdysiotropinecdysteroids and allatotropin-juvenile hormone). In crustaceans, a second-order inhibiting system comprises an ecdysiostatin

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and ecdysteroids. In all these cases, the central nervous system uses peptide hormones, liberins, or statins, for controlling glandular cells. Biosynthesis, processing. and secretion in peptidergic neurons are regulated on one hand by extrinsic and intrinsic stimuli through neurotransmitters, on the other hand by feedback actions through peripheric hormones (Fig. 3). How these messengers operate to turn on the protein precursor genes and to determine the appropriate processings, in other words how the various signals are integrated within the peptidergic neuron to give the precise answer, is poorly known. Regulatory mechanisms coordinating receptor signal transduction through the membrane have been investigated. One receptor can be modulated by a signalling mechanism initiated by a second distinct receptor. as found for insulin receptor and insulin-like growth factor II (IGF 11) receptor ( 14). Insulin receptor, besides triggering intracellular signalling pathway, stimulates lz51IGF II binding by increasing the number of its receptors (15). In the other hand, p-adrenergic inhibition of “‘l-insulin binding to adipocytes is due to a decrease in receptor affinity mediated by catecholamine receptors. Autophosphorylation of insulin receptor is also inhibited by catecholaminc. Interreceptor actions seem mediated by tyrosine protein kinases (IS). Howcvcr. the intracellular propagation of the signals remains still obscure. INDUCED NEUROHORMONAL CONTROL OF REPRODUCTION IN VERTEBRATES AND INVERTEBRATES A comparison can be made between the hormonal control of ovulation in the rabbit and that of egg release in a marine snail, the sea-hare Aplysia culifornicrt. In both species, mating initiates the reproductive mechanism. It can be assumed that in the rabbit, copulation stimuli are integrated in hypothalamic cells, determining a secretion of gonadoliberins (LH-RH). This hormone

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NEUROENDOCRINE

INTEGRATIVE

in turn acts on adenohypophysis provoking a secretion of follitropin (FSH) and lutropin (LH). These latter, in turn, act on ovaries causing ovulation and secretion of oestrogens and progesterone. In Aplysiu, the first hormones known to be involved in the control of egg release are produced by nonneural cells, forming the atria1 gland, a specialized part of the reproductive tract (IO, 16). These hormones, termed peptides A and B, have both 34 residues and differ only by four amino acids. They act on two clusters of neurons, the bag cells, stimulating secretion of a 36-residue peptide, the egg-laying hormone (ELH). This latter induces the egg release by ovotestis (Fig. 4). On the other hand, peptides of the bag cells, such as the CI and p bag-cell factors as well as ELH itself. are supposed to act as neurotransmitters altering the activity of specific neurons of the abdominal ganglion and triggering the innate egg-laying behavior. It is puzzling to note that in Aplysia, the first known hormone of the cascade is not produced by neural cells, which can integrate external and internal stimuli, as usually found for the other second-order neuroendocrine systems. It might be that secretion of the atria1 gland is itself under the control of a neuropeptide produced by one of the head ganglia. This putative peptide would be the equivalent of the mammalian hypothalamic gonadoliberin. Although a single gene has been found for human gonadoliberin precursor (17), three related genes forming the ELH multigene family have been discovered in Aplysia (5) (Fig. 2). Their protein products, ELH, peptide A and peptide B precursors, respectively, have in common a signal sequence and several regions of homology or close similarity. However, expression and processing differ according to the cell type since the nonneural atria1 gland produces peptides A and B whereas the bag cells manufacture ELH, (x and p factors and acidic peptide. Assuming that the ELH

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multigene family derives from a single ancestral gene by duplications and subsequent mutations, it appears that the evolutionary increase in complexity of the neuroendocrine integration may involve both intergene coordination, through cell differentiation, and intragene coordination, through multiple peptide-transmitter OI peptide - hormone precursors. The gene message, expressed by a protein product, appears composite and processing of the protein precursor into several pieces raises the question whether all fragments have a direct endocrine or transmitter function or some of them are “topogenie” sequences for the intracellular traffic of the precursor. It is difficult at the present time to explain a physiological integration in terms of gene structure. If the gene organizations of most polypeptide messengers have been established, very few receptor genes have up to now been sequenced and, principally. we do not know the rule permitting to deduce the conformations of the peptides or proteins from the deduced amino acid sequences. The interactions between polypeptide messengers and receptors depend upon the general rules of the protein-protein interactions and it is likely that a great similarity will be found between vertebrate and invertebrate systems when the respective conformations are known. REFERENCES I.

2.

3.

4. 5.

Lamarck. J. B. (1809). “Philosophic Zoologique”. Dentu, Paris, Part 1, reprinted by “Union Gtn&ale d’Editions” (1968) Paris. Acher, R. (1983). III “Brain Peptides” (Krieger. D., Brownstein, M. and Martin. J.. eds.). pp. 135-163. John Wiley and Sons. Acher, R. (1984). In “Evolution and Tumour Pathology of the neuroendocrine System” (I%lkmer. S., HBkanson, R.. and Sundler. S.. edb.). pp. 181-201. Elsevier Science Publishers B.V. Scharrer, B., and Scharrer, E. ( 1944). Biol. Bit//. 87, 242-25 I. Scheller, R. H., Rothman, B. S., and Mayeri. E. (1983). Trends NeuroSci. 6, 340-345.

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6. Dockray, G. J., and Gregory, R. A. (1980). Proc. R. Sot. Lond. B 210, 151-164. 7. Liotta, A. S., and Krieger, D. T. (1983). I~z “Brain Peptides” (Krieger, D., Brownstein, M., and Martin. J., eds.). pp. 613-660. John Wiley and Sons. 8. Numa, S., and Nakanishi, S. (1981). Trend5 Biochern. Sc,i. 4, 274-277. 9. Mains, R. E.. Eipper, B. A., Glembotski, C. C.. and Dores. R. M. (1983). Trends NerrroSc,i. 6, 229-235. IO. Strumwasser. E. Kaczmarek. L. K., Jennings, K. R.. and Chiu, A. Y. (1982). In “Neurosecretion: Molecules. Cells, Systems“ (Farner, D. S.. and Lederis, K.. eds.). pp. 249-268. Plenum. N.Y. II. Palade, G. ( 1975). Sc,ienc,e (Wrr.shiugton, D.C.) 189, 347-358. I?. Scharrer, E. (1966). I,I “Endocrines and the Central Nervous System” Vol. 43. pp. l-35. Associa-

ACHER tion for Research in Nervous and Mental Disease, Baltimore, The Williams and Wilkins Co. 13. Scharrer, E.. and Scharrer. B. (1963). “Neuroendocrinology.” Columbia Univ: Press. 14. Massague, J., and Czech, M. P. (1982). J. Biol. Chern. 257, 5038-5045. IS. Czech, M. P. (1984). 7th International Endocrinology, Excerpta Medica Congress Series 652, Abstract P.S.

Congress International

of

16. Strumwasser, F. (1984). In “Biosynthesis. Metabolism and Mode of Action of Invertebrate Hormones” (Hoffmann, J., and Porchet. M.. eds.). pp. 36-43. Springer Verlag, Berlin. 17. Seeburg. P. H., and Adelman, J. P. (1984). Ntrttrrc (London) 311, 666-669: Proceedings of the Ninth International Symposium on Neurosecretion (Kobayashi, H.. Bern, H. A., and Urano, K.. eds.). Japan Scientific Societies Press and Springer Verlag. in press. [Abstract S 1041