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220 11 ~,',S - Mav 198.' Segmentation and neural develolm' nt in Roger J. Keynes and Claudio D. Stern

A prominent feature of the development of most higher orgamsms ts the sub&wsion between antenor and postermr sclero- of the into a series of repeating elements, or segments. In vertebrates, the tome halves, rotation experiments degree to which the ts involved m thts process ts uncertain, and has were carried out s. First, a portion of received lmle attention recently. It may be relevant, however, to an understanding of neural tube opposite 2 or 3 was the mechanisms underlying neural development rotated 180" antero-posteriorly (A-P) prior to axon outgrowth, so that neural Segmentation in the embryo had Lehmann earher, that 'segmenta- tube previously opposite anterior half- is most obvious in the repeating pattern tion of the and peripheral semite came to lie opposite posterior of the somites, and this ~s reflected in nerves is entirely subservient to meso- half After 2 days of further develop- the adult by the serial arrangement of dermic segmentation and that an ment axons had still grown out through the vertebrae and their associated tntnnsic segmentation is non-existent ' the anterior halves of those somltes muscles, nerves, labs and blood vessels opposite the rotated neural tube It is also visible m the nervous system. Peripheral nerve segmentation in the Second, a portion of segmental plate Morphological segments in the neural chick embryo , 2-4 presumptive somltes tube were first noticed by yon Baer m In re-examimng these phenomena in long, was rotated 180 ° A-P, this time, 1828 I, and came to be called neuro- the chick embryo, we were interested after further development, axons had meres Subsequently some authors first to know how motor and sensory traversed the postenor (original anter- took them as evidence, additmnal to axons growing from the neural tube ior) halves of the grafted somltes the existence of somites, that verte- region are related to the somites, wluch Axons therefore grow through anter- brates evolved from a primitive seg- he in longitudinal senes adjacent to the ior half-sclerotome, regardless of its mented ancestor, and that the verte- neural tube Twenueth century text- position relative to the neural tube or to brate head has a segmental ongin 2_ books of descnbe the the A-P axis of the whole embryo However, this was not generally ac- spinal nerves of lugher vertebrates as These expenments confirm Lehmann's cepted 3,4 In particular, it was never developing either opposite the middle and Detwder's conclusion that seg- agreed whether , most of each semite, or between somites. It mented axonal outgrowth is due to the obvious m the region of the developing was therefore surprising to find, In zinc somites. In addition, they show that in hmdbrain (Fig 1), extend the full lodide-osmmm tetroxide stained, the chick segmentation is due to a rostro-caudal extent of the neural tube whole-mounted , that axons difference between anterior and pos- In a review on the subject in 1918, actually traverse the anterior (rostral) terior sclerotome cells Axons do not NeaP pointed out that 'there is not the half of the sclerotome of each serrate s grow out simultaneously along the slightest evidence that the neuromeres (and it was less surprising to find that length of the neural tube and then of the spinal cord are other than the this had been descnbed in 1855 by become secondarily segmented by the passive result of the mechamcal pres- Remak 9) (Figs 2, 3) To test whether developing sclerotome. Rather, they sure of the adjacent mesodermlc this segmented outgrowth occurs be- grow out in a punctuated manner, first somites'. Kallen s later produced some cause of intrinsic neural tube segmenta- axons exit opposite antenor half- ewdence that they represent locahsed tmn or because of some difference sclerotome, while later axons do exit regions of mitotic activity While Neal's opposite posterior half-sclerotome but statement continues to be vahd, the fasclculate on previously outgrown possibility that neuromeres have rather axons so as to diverge towards antenor more developmental significance re- half-sclerotome on either side s mains. In the earliest experimental studies cells on neural segmentation, Lehmarm Weston 1°, using [3H]thymidme auto- and Detwiler wanted to know how the radiography, originally descnbed the penpheral nerves become segmentally ventral pathway of migrating truncal arranged. Specifically, they wondered neural crest cells as being through whether this is because of external sclerotome, but later studies using the constraints imposed on the outgrowing quail-chick chunaera system n, or a axons by the somites, or because the monoclonal antibody 12, put the major neural tube is lntnnsically segmented pathway between adjacent somttes_ with respect to the position of out- More recently, lmmunohtstochemical growth. Lehmann found that removal studies have confirmed Weston's re- of several consecutive somites in sults Furthermore, they have shown urodele embryos leads to a loss of that neural crest cells share the segmentation of sensory ganglia in the Fig. 1. Neuromeres m an unfired, stage 21 chick pathway of motor axons by m~grating operated region Detwder then went embryo The hmdbram region of the neural tube pnmarily through the anterior half of was opened out by a dorsal cut along the mtdlme, on to show that grafting an addltmnal and ~everal segments () are visible each sclerotome (Rickmann, M , semite produces an additional spinal on each vide Photographed with reflected hght, Duband, J L, Fawcett, J W. nerve and ganglion He concluded, as × 200 Keynes, R. 1 and Thiery. J P , unpub-

~) 1985 Elsewer Soenoe Pubhshers B V Amsterdam 0378 5912/85/$(12 (~) TINS -May1985 221

stage when few or no sclerotome cells are present, motor axons have been described as being either between myotomes (Xenopus) or opposite the middle of the myotome At later stages, though, both motor and sensory axons and sensory ganglia are found in the anterior half-sclerotome. In apodan amphibia*, reptiles, and , axons grow out at a stage by which the sclerotome is well devel- oped, and it is hkely that in these higher vertebrate classes the A-P subdivision simultaneously determines axonal seg- mentation s One interesting feature of the A-P subdivision of the vertebrate somtte is its parallel with the insect segment Insect epidermal segments can be Fig. 2. Transverse semz-thm section of a late stage-16 chtck embryo, at the level of the wing somttes, subdivided into antenor and posterior stamed wtth toluldme blue By the stage of motor axon outgrowth (arrow), the somue has developed mto 'compartments 'I7 A compa,tment in dermatome, myotome (D, M, respecttvely presumpUve dermt~ and ) and selerotome (S, this sense has been defined as compris- presumpttve vertebral column) NT, neural tube, NC, Scale bar, 100 wn Reproduced with ing all the surviving descendants of a permission from Ref 8 ) small group of founder cells 17.1s We do hshed observations) (Fig 4) Fibronec- which occurs between axial muscles not know whether the anterior and tin, which has been suggested as being and vertebrae, both of which develop posterior sclerotome halves are also the controlling factor in the guidance of from the somites, Remak introduced developmental compartments, and the crest cells, IS localized mainly at the the concept of 'neughederung', or re- similarity IS, at best, a superficial one borders, as previously des- segmentation, whereby on each side of In Drosophila, a number of 'homo- crlbed 13, there was no detectable varia- the embryo the anterior half of one eotlc' genes have been Identified 19,2° tion in the A-P distribution of this mol- sclerotome merges rostrally with the whtch are believed to play a controlling ecule wsthln the somite This lmphes posterior half of the next sclerotome to role in the specification of segment that fibronectln does not play a critical form a vertebra That cells from one identity and polarity. For example, the role in determining the route taken by somtte can contnbute to two adjacent homoeottc gene engraded is revolved m crest cells or axons_ vertebrae has been confirmed recently determining the distinction between Since crest ceils precede motor axons using the quail-chick chimaera techm- posterior and anterior compartments m m the anterior half-sclerotome, one que is. However, the original descrip- Drosophda epidermal segments 2°_ A possibility would be that axons grow on tions of re-segmentation are open to short DNA sequence assocmted with crest cells However, surgical removal criticism I6, and further experiments several of these genes, which is of the neural crest does not alter the will be needed to examine this phenom- conserved in the vertebrate genome, segmented outgrowth of motor axons. enon in more detail It would appear, then, that whatever Whether the A-P subdivision deter- differences exist between anterior and mines axonal segmentation in all * The order Apoda comprises a group of legless posterior sclerotome cells and/or their vertebrates is less certain In and amphibians living in South America, tropical extracellular matrices, they can be amphibia, axons normally grow out at a Africa, the Seychelles and south east Asta detected independently by axons and neural crest cells_

Comparisons with other species Does an A-P subdivision of the somlte exist m all vertebrate classes? The answer is probably yes_ Since Remak's onginal description of the development of the vertebral column in the chick embryo 9, it has been con- firmed in all vertebrate classes that the sclerotome subdivides into anterior and postenor halves which subse- quently differ in cell density s In the chick, a boundary, first descnbed by von Ebner 14, can be seen separating the two halves of the sclerotome in the middle of each somtte_ This Won Fig. 3. Whole mount of stage-19 chick embryo, wing region, stained with zinc ~odlde-osmtum tetroxlde Ebner's fissure' ~s never crossed by Motor axons are seen having emerged from the neural tube (mfertor), and are confined to the anterior axons In order to explain the overlap (left in the figure) halve~ of the somttes The somtte borders are enclosed by astertsks Scale bar, 50 ~n 222 l t,~,A Mav l gN5

has recently been discovered and is known as the homoeo bOX21"22 This has NeuralTu~ ee ~fi/..~ "~ ~ ~.~ Dorsal Root Gangm I n led to the speculation that the devel- opmental mechanisms which underlie segmentation in insects and vertebrates might be similar. Several homoeotlc- like mutations affecting the develop- SomlteMy otome- ~(~I ~ '} 1) ! ment of body segments have been identified m mouse embryos 23 How- Sclerotome---~ ~ )_ /~ ever, it is not yet known whether the vertebrate homoeo box is assocmted with, let alone restricted to, homolo- gous homoeotic genes controlling so- Notochord~ mite dlverslficatmn Moreover, seg- mentation could have evolved inde- pendently m and arthropods, their common ancestor being unseg- Aorla mented_ If so, the underlying mechan- isms may turn out to be rather [~. 4. Dutgram showing the major path ways of truncal crest cell mlgranon and axon growth m the chzck embryo The somJte :s dispersed into Its three components (see F~g 2) Neural crest cells (heavy arrows) different mLgrate from the dorsal aspect of the neural tube into the anterior (left m the figure) half o[ each somlte Segmentation and axonal guidance They pass both between the dermomyotome and sclerotome and through the sclerotome itself, before becoming component~ of the autonormc nervous system Some remain m the anterior half-sderotome The earliest guidance of outgrowing and develop into dorsal root ganghon cells Sensory axons, which ar~se from the dorsal root ganghon axons in somlte regions of the chick cells, are therefore confined to the anterior half-sclerotome, as are the motor axons embryo is non-specafic, in the sense that any axon, whether motor or The process of emigration ends well genetic and ontogenetlc mochficatlon, sensory, will grow through any anterior before axons sort out, for example, m may surely be considered as estab- half-sclerotome. Opposite limb re- the chick leg, muscle cells cease to lished The motor plexus of a hmb gions, motor axons from different leave the somites at about stage 20 ~s brought about, not by the nerve nelghbouring motor pools of the spinal (Ref 29), whilst axon sorting starts deserting one muscle for the sake of cord, destined for different limb after stage 23, or almost 24 h later 24 another, but by the coml~nation of muscles, are mtxed with each other Since the site of axon sorting hes muscles derived from neighbouring within each ventral root 24. Could adjacent to the ventral edges of the segments.' The experiments of Wigston segmentaaon be involved m any more dermomyotomes, guidance cues might and Sanes 33 do suggest that the specific way in the guidance of axons9 be m the form of trails of extracellular segmentally derived intercostal It seems possible that it could. Motor matrix molecules provided by the muscles retain some label, perhaps axons can be guided by specific cues to muscle cells that earlier migrated segmentally deternnned, which biases their correct limb muscles; for exam- through this regton ~°. Alternatwely, the lnnervation they receive. It is, ple, after 180 ° A-P rotation of a length muscle cells themselves could still be nevertheless, equally possible that of neural tube opposite 3 to 5 leg present here, providing cellular trails muscle cells are specified after leaving som~tes, motor axons are still able to for axons to follow into the hmb muscle the sonutes by a system set up within project to their correct muscles zs. masses Such a muscle cell trail, also the hmb itself, or that non-muscle ceils Lance-Jones and Landmesser 24, using somite derived, precedes the out- provide the cues instead. It should be orthograde and retrograde HRP trac- growth of axons of the hypoglossal possible to dlstingtush between these ing, have shown that motor axons nerve, in what could be an analogous alternatives experimentally normally sort out at the root of the developmental system 3I The results of embryonic manipula- limb, m the regmn of the developing Either way, for muscle cells to tions25-27 suggest that motor axons are nerve plexus_ This is also the region provide specific cues requires that they also labelled to allow them to recogmse where axons sort out following a be appropriately labelled They might, their guidance cues, but the basis for variety of experimental manipula- for example, be specified on an A-P this is unknown. As far as the A-P axis tions 25-27 As a result of this process, basis according to their somlte of is concerned there are perhaps two axons from a given muscle's motor origin, and carry this label into the major possibilities First, that there is a pool, which project out m more than limb: motor axons of the same seg- graded continuous rostro-caudal label- one ventral root, are collected to- mental level may then assocmte with ling system extending down the neural gether, and they remain together as these cells in preference to those of a tube, and second, that there is a they grow towards the developing different segmental origin. This possi- discontinuous system, arising on the muscle. bility, of continuous segmental match- basis of intrinsic segmentation within In considenng possible sources of mg between motor nerves and myo- the neural tube While Detwiler con- specific guidance for motor axons it tomes within the te~apod limb, was cluded that mtrinmc segmentation is would be interesting to know what cell first tamed by Goodrich 32, arguing by non-existent, neither his nor our exper- types axons encounter as they undergo analogy with the innervation of fin iments on peripheral nerve outgrowth this sorting process. One possibility is muscles. Indeed, he felt able to say in in fact exclude it with respect to the that muscle cells provide these cues 1906 'That in a series of metamenc development of neurons within the Muscle cells migrate into the limb from myotomes and nerves each motor neural tube. The existence of neuro- the ventral edges of those dermo- nerve remains faithful to its myotome, meres at least hints at this posslblhty, myotomes opposite the limb bud 2a throughout the vicissitudes of phylo- and there are descriptions of segmen- TINS- May 1985 223 tally arranged neurons in the adult Selected references 409-414 spinal cord of Amphloxus 34 and several 1 yon Baer, K E (1828) Uber&e Entwlcklung- 23 Gruneberg, H (1963) The pathology of vertebrates 35,36 In this hght it is sgeschschte der Thtere, Komgsberg development, Blackwell, Oxford 2 Hdl, C (1899) Anat Anz 16, 353-369 24 Lance-Jones, C and Landmesser, L (1981) perhaps worth notmg that the neuro- Proc R Soc (London)Set B 214, 1-18 meres of the spinal cord lie out of 3 Neal, H V (1918)J Morphol 31,293-315 4 Streeter, G L (1933) J Comp Neurol 57, 25 Lance-Jones, C and Landmesser, L (1981) register with the somltes by a distance 455-475 Proc R Soc (London)Set B 214, 19-52 of half a somite 5 Kallen, B (1952) Acta Soc Med Ups 57, 26 Ferguson, B A (1983) J Neurosct 3, 1760- There is, as yet, no evidence that the 111-118 1770 other elements of the peripheral ner- 6 Lehmann, F (1927) J Exp Zool 49, 93-131 27 Stlrhng, R V (1983) m Limb development vous system (the cranial, autonomic 7 Detwder, S R (1934)J Exp Zool 67,395- and regeneration, Part A (Fallon, J F and Caplan, A I , eds), pp 217-226, A R Liss and spinal sensory axons) are position- 441 8 Keynes, R J and Stem, C D (1984) Nature Inc, New York ally specified prior to axon outgrowth (London) 310,786-789 28 Chevalller, A , Kleny, M and Mauger, A m the way that spinal motor axons are 9 Remak, R (1855) Untersuchungen uber die (1977)J Embryol Exp Morph 41,245-258 A-P selectivity between regenerating Entwtcklung der WIrbelthlere, Relrner, Berhn 29 Jacob, M, Christ, B and Jacob, H J (1979) pre-ganghonic sympathetic axons and 10 Weston, J A (1963) Develop Blol 6, 279- Anat Embryol 157, 291-309 post-ganghomc cells has, however, 310 30 Landmesser, L (1984) Trends NeuroSct 7, been demonstrated 37 In addition, in 11 LeDouann, N (1982) The neural crest, 336-339 31 Hunter, R P (1935)J Morphol 57,473--499 both the sympathetic and parasympa- Cambndge Umverslty Press, Cambndge 12 Vincent, M and Thlery, J P (1984) Dev 32 Goodnch, E S (1906)Q J Micros Scl 50. thettc systems, the sections of the B~ol 103, 468--481 333-376 neural tube which contribute pre- and 13 Thlery, J P , Duband, J L and Delouv6e, 33 W~gston, D and Sanes, J R (1982) Nature post-ganglionic cells are broadly equi- A (1982)Dev Blol 93, 324-343 (London) 299, 464-467 valent along the A-P axis 11, These 14 yon Ebner, V (1888) Sltzungsber Akad 34 Bone, Q (1960)J Comp Neurol 115,27-64 phenomena, and the striking seg- Wtss W~en 97, 194-206 35 Whiting, H P (1948)Q J Micros Sc~ 89, 15 Beresford, B (1983) J Embryol Exp 359-384 mented pattern of cutaneous lnnerva- 36 Huber, J F (1936)J Comp Neurol 65,43- tlon 38,~°, could reflect an underlying Morph 77, 99-116 16 Verbout, A J (1976) ActaBtotheor 25,219- 91 recognition system based on segmental 258 37 Purves, D , Thompson, W and Yip, J W matching While the process of seg- 17 Garcla-Belhdo, A, R~poll, P and Morata, (1981) J Phystol (London) 313, 49-63 mentation certainly influences the G (1973) Nature (London) New Btol 245, 38 Diamond, J (1982) m Current topics m earhest axon outgrowths, tt remains to 251-253 developmental biology, Vol 17 (Moscona, A A and Monroy, A, eds), pp 147-205, be seen whether tt continues to play a 18 Lawrence, P A (1973) J Embryol Exp Morph 30, 6814i99 Academic Press, New York role m shaping neural development at 39 Seott, S A (1982)J Physlol (London) 330, later stages. 19 Lewis, E B (1978) Nature (London) 276, 565-570 203-220 20 Morata, G and Lawrence, P A (1975) Acknowledgements Nature (London) 255,614-617 We thank R Victoria Stlrhng and 21 McGmms, W, Garber, R L, Wlrz, J, Roger J Keynes ~s ln the Department of , Michael Bate for comments on the manu- Kurolwa, A and Gehnng, W J (1984) Cell Downing Street, Cambridge CB2 3DY, UK script, Ralth Overhdl for Ftg_ 4, and John 37,403~08 Claudto D Stern is in the Department of Bashford and Roger Ldes for help with 22 Carrasco, A E, McGmnis, W, Gehrlng, Anatomy, South Parks Road, Oxford OXI 3QX, photography W J and de Roberus, E M (1984) Cell37, UK

Theory in Psychopharmacology: The general quahty of the contribu- m the nervous system. Although the Vol. 2 tions is excellent the chapters by contributions are not aimed at present- Cooper and Sanger are particularly ing new data, they are well-illustrated edited by S_ J Cooper, Academic good critical evaluations of current by figures representing important find- Press, 1983 US$45 00/£25 O0 (x + 247 hypotheses about the mechanisms lngs, and a comprehenstve biblio- pages) ISBN 0 12 188002 8 underlying drug effects on feeding and graphy follows each article The second volume of 'Theory In dnnkang, and the chapter by Rupnlak, Each of the articles stimulates Psychopharmacology' contains six Jenner and Marsden provides a much- thought and illustrates important ques- chapters by authors who are well needed cnticlsm of the hypothesis that tions of theory and methodology, both known and active researchers m the dysfunction of the 's dopamme general and specific, that can be field, and is well balanced between systems underlies schizophrenic dis- applied to several areas of psycho- contributors with a predominantly orders, a theory that is stdl presented pharmacological research Psycho- psychological, and those with a pre- as accepted m general pharmacology pharmacology (behavioural pharma- dominantly pharmacological, back- courses, but against which consider- cology) is a science that is concerned ground The aim of the volume, and able evidence is amassing The other with the interacttons between drugs one in which it succeeds admirably, ts fields of research covered in the and behaviour, and thus can be to review the background to areas of present volume are endogenous modu- approached from at least two stand- research that are currently prominent, lation of learning and memory, corre- points One approach is to study the and to relate the empirical data that lations between activity of serotoner- ways in which drugs can produce has been produced to theones about gic systems in the CNS and behaviour, changes m behaviour, another ap- how the effects of a drug on behaviour and the discriminative stimulus prop- proach is to study the way m which may be achieved_ erties of drugs acting at opiate systems behavtoural factors (for example, past