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Flies and worms: molecular genetic approaches to neurobiology
TINS-June1985
229
Introduction Flies and worms: molecular genetic approaches to neurobiology Corer S. Goodman The neurobtology of Drosophila melanogaster and Caenorhabditis elegans, inIt,ated nearly two decades ago respecuvely by Seymour BenzerI and Sidney Brenner2, has finally come of age Kindled by the apphcaaon of genenc approaches to neurobtology, and fuelled by the infusion of modern recombinant DNA and monoclonal antibody approaches, the last few years have witnessed an enormous explosion of interest In the neurob,ology of these two organ~ms Although several rev,ews on flles and worms have already appeared m TINS J-H, and many more will surely come, this special issue represents a collection of essays tamed at covering a wide range of topics on nerve and muscle function and development m these two organisms Why flies and worms for a special issue of TINS 9 Afficlanados often argue a b o u t the relative virtues of one v the other, but no one argues that for genetic approaches to the study of multicellular orgamsms they are unrivalled A m o n g their shared attnbutes are small genomes (the haploid D N A content of each is only about one order of magnitude greater than bacteria, and at least one order of m a g m t u d e smaller than man), relatively small numbers of genes (worms are estimated to have 3-5000 genes, whereas flies are estimated to have 510 000 genes), rapid and prolific reproductlon, and a small n u m b e r of linkage groups (worms have six pairs of c h r o m o s o m e s and flies have four) In addition to the classical methods of genetics and molecular biology, the advent of transposable elements as tools for mutagenesis and DNAm e d i a t e d gene transfer (see Rubin, this issue) allows many e x p e n m e n t a l approaches to molecular neuroblology that are not currently feasible in other organisms But are their nervous systems built like o u r s 9 0 b w o u s l y , they do not look or act like us They do not have an area 17 of visual cortex, or a supenor cervical ganglion for that matter But they do have precisely wired multicellular nervous systems whose synapses function using many of the same channels, transmitters and receptors, and develop using many of the same cellular and molecular mechanisms, as does our own During embryonic development, their neurons form specific synaptlc connections with remarkable precision; after birth, these synaptic connechons exhibit a wide range of plasticity, rearranging as a result of further development and changing as a result of experience (for
example, Refs 3, 4, 10-16) Although relatively simple, the nervous systems and behavior of these two lower animals thus afford sufficient nchness and complexity to allow us to ask m a n y of the same questions associated with the more complex nervous systems of higher ammals Of course, not everything can be studied in simple organisms, some properties emerge as a result of the increasing orders of magnitude of neurons in higher organisms Furthermore, in some cases, we just do not yet have enough information to make a fair c o m p a n s o n Without further studles, for example, it is difficult to predict the extent to which trophlc factors, competition, and activity-dependent events and/or may not play a role in the control of cell death, synapse rearrangement, and other systems matching mechanisms In these lower organisms Interestingly, the recent cloning of the epidermal growth factor ( E G F ) receptor homolog in flies 17 may now make it possible to isolate growth factors and elucidate their role d u n n g Drosophda development (whether trophic factors can also be identified remains to be seen) But as long as the questions asked are appropriate, reductlonist approaches using these simple organisms will provide an ever increasing understanding of the cellular and molecular mechanisms underlying neuronal structure, function and development Given the current interest in the molecular neuroblology of these two organisms, it is remarkable to consider just how few reviews on them have previously appeared in these pages_ It was in 1980 that the first article on Drosophila appeared in a special TINS issue on genetic approaches in neurobiology 3, it was only last year that the
first article (and centerfold) on Caenorhabdi~ appeared in TINS 4 Although their numbers have been limited, over the last few years several excellent reviews and journal clubs on Drosophda neurobiology have appeared In TINS on growth cone guidance 5,6, potassium channels 7, synaptic specificity s, homeotic genes 9, and plasticity l°,lI Given the excitement in the field, the TINS Editorial Board decided to devote a special issue to Drosophda melanogaster and Caenorhabdltis elegans (with a few notes on their big brothers, grasshopper and Ascaris) We Include such topics as transposable elements as genetic tools (Rubin, this Issue), genes encoding excitable channels (Jan et aL), neuronal circuits and connectivity (Stretton et al; White), pattern formation (Lawrence), homeOtlC genes (Levlne and Wedeen), muscle development (Waterston and Francis), neurogenic genes (CamposOrtega), genes controlling cell lineage (Hedgecock), development of the fly eye (Venkatesh et aL), and growth cone guidance and cell recognition (Blair and Palka, Bastlani et al ) Unfortunately, as is always the case in organizing such an issue, we run the risk of offending those left out because of space and time limitations, it was impossible to include every topic we would have hked to have seen in this specml ~ssue. Many topics of current interest, such as circadian rhythms TM and phototransductlon 19,2°, to name just two, will have to await future issues But for the present, this collection of reviews should give a good glimpse of what IS going on in the field Of course, this issue represents only the tip of the iceberg The potential for molecular genetic approaches to neurobiology, and in particular to our understanding of neuronal development, IS just beginning to unfold, and these two organisms will likely play a key role For many years now developmental geneticists such as Ed L e w i s 21,22 have been using genetic approaches to isolate mutations in genes, such as the blthorax complex, which control important development decisions In the last few years, the
r~ 198~, Elsevier Science Pubhsher~ B V
Am~[crdarn
()t7~
~912/8s/$(12 (~)
230 genetic approach to developmental biology has finally come to frmtlon as rapid progress has been made in the isolation and characterization of developmentally important genes m fl~es and worms controlhng, for example, positional reformation z3, segmentation 24-26, segment identity 27-1~, and cell hneage 32,33_ A n d the latest craze, 'homeo-madness '3w37, Is spreading like an epidemic (see Levlne and Wedeen, this issue), 'homeo box' homologies have been identified m genes throughout the animal kingdom 3~41 We can only hope that as much progress will be made over the next five years in understanding the development of the nervous system, as has been made over the last five m unravelhng the development of segments and segment identities in Drosophila One thing is for certain tt ~s doubtful that this will be the last time TINS focuses on these two organisms
Selected references 1 Benzer, S (1971) J A m Med Assoc 218, 1015-1022 2 Brenner. S (1973)Br Med Bull 29, 269271 3 Dudal, Y and Qumn, W G (1980) Trends NeuroSct 3, 28--30 4 Chalfie, M (1984) Trends NeuroSct 7, 1972O2 5 Bate, M (1982) Trends NeuroScl 5,140-141 6 Palka, J and Ghysen, A (1982) Trends NeuroSct 5. 382-386
I I N 3 - J u n e 1985
7 Salkolf, L and Wyman R (1983) Frends 27 Bender, W , Akdm, M , Karch, F Beach,,, NeuroScl 6, 128-133 P A , Peffer. M , Splerer, P , Lewis F B 8 Thomas, J B and Wyman, R (1983) and Hogness, D S (1983)3ctence 221, _~, Trends NeuroSct 6. 214-219 29 9 Scott, M (1984) Trends NeuroSct 7. 22128 Lawrence P A and Morata G [19~3)t'e/l 223 35, 595-601 10 Palka, J (1984) Trends NeuroSct 7,455-456 29 Scott, M P , Wemer, A J Hazelngg. 11 Dudal. Y (1985) Trends NeuroScl 8, 18-21 T I. Pohsky, B A P~rrotta. V 12 White, J G , Albertson, D G and Anness, Scalenghe, F and Kaufman. F C (1983) M A R (1978) Nature (London) 271,764Cell 35,763-776 766 30 Garber, R L , Kuro~wa, A and Gehrmg, 13 Sehne~erman, A M , Matsumoto, S G W J (1983) E M B O J 2, 2027-2036 and Hildebrand, J G (1982) Nature (Lon31 Beachy, P A , Helfland, S L and Hogness, don) 298, 84~846 D S (1985) Nature (London) 313, 545-551 14 Lewne, R B and Truman, J W (1983) 32 Greenwald, I S , Sternberg, P W and Nature (London) 299, 477-479 Horvltz, H R (1983) Cell 34, 435 4A~4n 15 Qulnn, W G and Greenspan, R J (1984) 33 Ambros, V and Horvltz, H R (1984) Annu Rev Neurosct 7, 67-93 Science 226 409-416 16 Technau, G M (1984) Neurogenet 1, 113- 34 McGmms, W . Lewne, M S , Hafen, E . 126 Kurolwa, A and G e h n n g W J (1984) 17 LJvneh, E , Glazer, L , Segal, D , SchlesNature (London) 308, 428--433 singer, J and Shdo. B-Z (1985) Cell 40, 35 Laughon, A and Scott, M P (1984) Nature 599-607 (London) 310, 25-31 18 Zehnng, W A , Wheeler, D A , Reddy, 36 Poole, S J , Kauvar, L M , D r e e s , B and P . Konopka, R J , Kynacou, P , Rosbash, Kornberg, T (1985) Cell 40, 37-43 M and Hall, J C (1984) Cell 39, 369-376 37 Gehrmg, W J (1985) Cell 40, 3-5 19 O'Tousa, J E , Baehr, W , M a r t m , R L , 38 Shepherd, J C W, McGmms, W, H~rsh, J , Pak. W L and Applebury, M L Carrasco, A E , De Roberhs, E M and (1985) Cell 40, 839-850 Gehnng, W J (1984) Nature (London) 310, 20 Zuker, C S , Cowman, A F and Rubm, 70-71 G M (1985) Cell 40, 851-858 39 Levme, M . Rubm, G M and T1jlan, R 21 Lewis. E B (1963) Am. Zool 3, 33--56 (1984) Cell 38, 667--673 22 Lewis, E B (1978) Nature (London) 276, 40 McGmms, W , Hart, C P , Gehrmg, W J 565-570 and Ruddle, F H (1984) Cell 38, 675--680 23 Anderson, K V and Nusslem-Volhard, C 41 Muller, M M , Carrasco. A E and De (1984) Nature (London) 311,223-227 Robertis, E M (1984) Cell 39, 157-162 24 Nusslem-Volhard, C and Wlesehaus, E (1980) Nature (London) 287, 795-801 25 Hafen, E , Kuroxwa, A and Gehnng, W J (1984) Cell 37, 833~41 26 Prelss, A , Rosenberg, U B , IZ,aenlin, A , Corey S Goodman ~ tn the Depar~nent of Seifert, E and Jackle, H (1985) Nature Biologtcal Scwnces, Stanford Umverszty, Stan(London) 313, 27-32 ford, CA 94305, USA
229
Introduction Flies and worms: molecular genetic approaches to neurobiology Corer S. Goodman The neurobtology of Drosophila melanogaster and Caenorhabditis elegans, inIt,ated nearly two decades ago respecuvely by Seymour BenzerI and Sidney Brenner2, has finally come of age Kindled by the apphcaaon of genenc approaches to neurobtology, and fuelled by the infusion of modern recombinant DNA and monoclonal antibody approaches, the last few years have witnessed an enormous explosion of interest In the neurob,ology of these two organ~ms Although several rev,ews on flles and worms have already appeared m TINS J-H, and many more will surely come, this special issue represents a collection of essays tamed at covering a wide range of topics on nerve and muscle function and development m these two organisms Why flies and worms for a special issue of TINS 9 Afficlanados often argue a b o u t the relative virtues of one v the other, but no one argues that for genetic approaches to the study of multicellular orgamsms they are unrivalled A m o n g their shared attnbutes are small genomes (the haploid D N A content of each is only about one order of magnitude greater than bacteria, and at least one order of m a g m t u d e smaller than man), relatively small numbers of genes (worms are estimated to have 3-5000 genes, whereas flies are estimated to have 510 000 genes), rapid and prolific reproductlon, and a small n u m b e r of linkage groups (worms have six pairs of c h r o m o s o m e s and flies have four) In addition to the classical methods of genetics and molecular biology, the advent of transposable elements as tools for mutagenesis and DNAm e d i a t e d gene transfer (see Rubin, this issue) allows many e x p e n m e n t a l approaches to molecular neuroblology that are not currently feasible in other organisms But are their nervous systems built like o u r s 9 0 b w o u s l y , they do not look or act like us They do not have an area 17 of visual cortex, or a supenor cervical ganglion for that matter But they do have precisely wired multicellular nervous systems whose synapses function using many of the same channels, transmitters and receptors, and develop using many of the same cellular and molecular mechanisms, as does our own During embryonic development, their neurons form specific synaptlc connections with remarkable precision; after birth, these synaptic connechons exhibit a wide range of plasticity, rearranging as a result of further development and changing as a result of experience (for
example, Refs 3, 4, 10-16) Although relatively simple, the nervous systems and behavior of these two lower animals thus afford sufficient nchness and complexity to allow us to ask m a n y of the same questions associated with the more complex nervous systems of higher ammals Of course, not everything can be studied in simple organisms, some properties emerge as a result of the increasing orders of magnitude of neurons in higher organisms Furthermore, in some cases, we just do not yet have enough information to make a fair c o m p a n s o n Without further studles, for example, it is difficult to predict the extent to which trophlc factors, competition, and activity-dependent events and/or may not play a role in the control of cell death, synapse rearrangement, and other systems matching mechanisms In these lower organisms Interestingly, the recent cloning of the epidermal growth factor ( E G F ) receptor homolog in flies 17 may now make it possible to isolate growth factors and elucidate their role d u n n g Drosophda development (whether trophic factors can also be identified remains to be seen) But as long as the questions asked are appropriate, reductlonist approaches using these simple organisms will provide an ever increasing understanding of the cellular and molecular mechanisms underlying neuronal structure, function and development Given the current interest in the molecular neuroblology of these two organisms, it is remarkable to consider just how few reviews on them have previously appeared in these pages_ It was in 1980 that the first article on Drosophila appeared in a special TINS issue on genetic approaches in neurobiology 3, it was only last year that the
first article (and centerfold) on Caenorhabdi~ appeared in TINS 4 Although their numbers have been limited, over the last few years several excellent reviews and journal clubs on Drosophda neurobiology have appeared In TINS on growth cone guidance 5,6, potassium channels 7, synaptic specificity s, homeotic genes 9, and plasticity l°,lI Given the excitement in the field, the TINS Editorial Board decided to devote a special issue to Drosophda melanogaster and Caenorhabdltis elegans (with a few notes on their big brothers, grasshopper and Ascaris) We Include such topics as transposable elements as genetic tools (Rubin, this Issue), genes encoding excitable channels (Jan et aL), neuronal circuits and connectivity (Stretton et al; White), pattern formation (Lawrence), homeOtlC genes (Levlne and Wedeen), muscle development (Waterston and Francis), neurogenic genes (CamposOrtega), genes controlling cell lineage (Hedgecock), development of the fly eye (Venkatesh et aL), and growth cone guidance and cell recognition (Blair and Palka, Bastlani et al ) Unfortunately, as is always the case in organizing such an issue, we run the risk of offending those left out because of space and time limitations, it was impossible to include every topic we would have hked to have seen in this specml ~ssue. Many topics of current interest, such as circadian rhythms TM and phototransductlon 19,2°, to name just two, will have to await future issues But for the present, this collection of reviews should give a good glimpse of what IS going on in the field Of course, this issue represents only the tip of the iceberg The potential for molecular genetic approaches to neurobiology, and in particular to our understanding of neuronal development, IS just beginning to unfold, and these two organisms will likely play a key role For many years now developmental geneticists such as Ed L e w i s 21,22 have been using genetic approaches to isolate mutations in genes, such as the blthorax complex, which control important development decisions In the last few years, the
r~ 198~, Elsevier Science Pubhsher~ B V
Am~[crdarn
()t7~
~912/8s/$(12 (~)
230 genetic approach to developmental biology has finally come to frmtlon as rapid progress has been made in the isolation and characterization of developmentally important genes m fl~es and worms controlhng, for example, positional reformation z3, segmentation 24-26, segment identity 27-1~, and cell hneage 32,33_ A n d the latest craze, 'homeo-madness '3w37, Is spreading like an epidemic (see Levlne and Wedeen, this issue), 'homeo box' homologies have been identified m genes throughout the animal kingdom 3~41 We can only hope that as much progress will be made over the next five years in understanding the development of the nervous system, as has been made over the last five m unravelhng the development of segments and segment identities in Drosophila One thing is for certain tt ~s doubtful that this will be the last time TINS focuses on these two organisms
Selected references 1 Benzer, S (1971) J A m Med Assoc 218, 1015-1022 2 Brenner. S (1973)Br Med Bull 29, 269271 3 Dudal, Y and Qumn, W G (1980) Trends NeuroSct 3, 28--30 4 Chalfie, M (1984) Trends NeuroSct 7, 1972O2 5 Bate, M (1982) Trends NeuroScl 5,140-141 6 Palka, J and Ghysen, A (1982) Trends NeuroSct 5. 382-386
I I N 3 - J u n e 1985
7 Salkolf, L and Wyman R (1983) Frends 27 Bender, W , Akdm, M , Karch, F Beach,,, NeuroScl 6, 128-133 P A , Peffer. M , Splerer, P , Lewis F B 8 Thomas, J B and Wyman, R (1983) and Hogness, D S (1983)3ctence 221, _~, Trends NeuroSct 6. 214-219 29 9 Scott, M (1984) Trends NeuroSct 7. 22128 Lawrence P A and Morata G [19~3)t'e/l 223 35, 595-601 10 Palka, J (1984) Trends NeuroSct 7,455-456 29 Scott, M P , Wemer, A J Hazelngg. 11 Dudal. Y (1985) Trends NeuroScl 8, 18-21 T I. Pohsky, B A P~rrotta. V 12 White, J G , Albertson, D G and Anness, Scalenghe, F and Kaufman. F C (1983) M A R (1978) Nature (London) 271,764Cell 35,763-776 766 30 Garber, R L , Kuro~wa, A and Gehrmg, 13 Sehne~erman, A M , Matsumoto, S G W J (1983) E M B O J 2, 2027-2036 and Hildebrand, J G (1982) Nature (Lon31 Beachy, P A , Helfland, S L and Hogness, don) 298, 84~846 D S (1985) Nature (London) 313, 545-551 14 Lewne, R B and Truman, J W (1983) 32 Greenwald, I S , Sternberg, P W and Nature (London) 299, 477-479 Horvltz, H R (1983) Cell 34, 435 4A~4n 15 Qulnn, W G and Greenspan, R J (1984) 33 Ambros, V and Horvltz, H R (1984) Annu Rev Neurosct 7, 67-93 Science 226 409-416 16 Technau, G M (1984) Neurogenet 1, 113- 34 McGmms, W . Lewne, M S , Hafen, E . 126 Kurolwa, A and G e h n n g W J (1984) 17 LJvneh, E , Glazer, L , Segal, D , SchlesNature (London) 308, 428--433 singer, J and Shdo. B-Z (1985) Cell 40, 35 Laughon, A and Scott, M P (1984) Nature 599-607 (London) 310, 25-31 18 Zehnng, W A , Wheeler, D A , Reddy, 36 Poole, S J , Kauvar, L M , D r e e s , B and P . Konopka, R J , Kynacou, P , Rosbash, Kornberg, T (1985) Cell 40, 37-43 M and Hall, J C (1984) Cell 39, 369-376 37 Gehrmg, W J (1985) Cell 40, 3-5 19 O'Tousa, J E , Baehr, W , M a r t m , R L , 38 Shepherd, J C W, McGmms, W, H~rsh, J , Pak. W L and Applebury, M L Carrasco, A E , De Roberhs, E M and (1985) Cell 40, 839-850 Gehnng, W J (1984) Nature (London) 310, 20 Zuker, C S , Cowman, A F and Rubm, 70-71 G M (1985) Cell 40, 851-858 39 Levme, M . Rubm, G M and T1jlan, R 21 Lewis. E B (1963) Am. Zool 3, 33--56 (1984) Cell 38, 667--673 22 Lewis, E B (1978) Nature (London) 276, 40 McGmms, W , Hart, C P , Gehrmg, W J 565-570 and Ruddle, F H (1984) Cell 38, 675--680 23 Anderson, K V and Nusslem-Volhard, C 41 Muller, M M , Carrasco. A E and De (1984) Nature (London) 311,223-227 Robertis, E M (1984) Cell 39, 157-162 24 Nusslem-Volhard, C and Wlesehaus, E (1980) Nature (London) 287, 795-801 25 Hafen, E , Kuroxwa, A and Gehnng, W J (1984) Cell 37, 833~41 26 Prelss, A , Rosenberg, U B , IZ,aenlin, A , Corey S Goodman ~ tn the Depar~nent of Seifert, E and Jackle, H (1985) Nature Biologtcal Scwnces, Stanford Umverszty, Stan(London) 313, 27-32 ford, CA 94305, USA