Pattern, symmetry and surprises in the development of Caenorhabditis elegans

Trends in Biochemical Sciences October 1983

Pattern, symmetry and surprises in the development of

Journal Cluh

Caeno rhabditis e legans

In the course of metazoan development, the quences of multiple developmental decisions. generation of multiple cell types from a Patterns emerge that may reflect underlying single cell requires the repeated creation of local strategies. Unique and unexpected daughter cells that differ from one another. This production of non-equivalent daughter m,o cells can be called a developmental decision, or switch. The task of understanding development is that of determining how MS these switches are arranged in space and time, and then how they operate at a r molecular level. A valuable way to identity possible switch points is to determine cell lineages, that is, the sequence of cell divisions that produces differentiated cells. By looking 2oofor relationships between cell fates and cell lineages we might he able to guess where developmental decisions take place. For example, a decision point might he a position at which daughter cells behave differ300ently in terms of the progeny they produce. By manipulating the cells genetically or physically it may be possible to verify that a developmental switch does in fact exist, 40oand to begin to learn how it operates. Cell lineages in the nematode Caenorhabditis elegans can he determined precisely. This organism develops with an invariant sequence of divisions and dif- ~0oferentiations, and individual nuclei can be ~3D observed in living animals using Nomarski optics. Using this technique, John Sulston has recently completed a spectacular feat. At the rate of about one cell per day, he has 600 determined the lineal descent of all 558 cells (and 113 programmed cell deaths) in the newly hatched larva 1. Together with the Fig. l. A portion of the embryonic lineage of Caenorhabditis elegans. Cells of a single type can arise ( 1) from a lineages that describe the developmental single precursor: the E founder cell generates all the intestinal cells; (2) in many small families; examples are sequence from hatching to maturity 2.3, the the small body muscle clones and the pair of sister coelomocytes; or (3) non-elonally, as does the intestientire cell lineage of a complex multicellu- nal muscle. Likewise, organs that contain distinguishable cell types can arise (1) clonally; for example, Z1 lar organism is now known (see Figs 1 and produces one of the two arms of the gonad (see Fig. 2); or (2) non-clonally; for instance the pharynx (esophagus) is built from multiple precursors. The families of pharyngeal cells shown here contain neurons, 2). muscle cells and structural cells. Finally, pictured here (X) are 8 of the 113 embryonic cells that undergo Recorded in the lineage are the conse~ programmed cell death. 100

--

i

_L

1

t

H

1983, Elsevier Science Publishers B.V., Amsterdam

0376 - 5067/83/$01 .CO

350

T1BS - October 1983

4


7

~

c ~

S

~7

~

127

~ ~ ~.~ ~

~ 2~ ~ "~ ~ ~

~ ~.~

. ~ ~ ~ ~.~

events occur as well. These patterns (and irregularities) provide insight into the organization of development (for more comprehensive discussions, Refs 1-5, 7). In C. e l e g a n s the first major determinative events take place at the first divisions. These cleavages create 6 founder cells, each capable of producing only a subset of cell types. One produces all 20 endodermal (gut) cells; another cell produces the 2 000 germ (sperm, oocyte) cells. Classical studies had suggested that the first divisions created founder cells producing strictly endodermal, germ, ectodermal (neurons, epidermis) or mesodermal (muscles, gonads) descendants (see Ref. 6). Thus it was surprising to find that the early separation of ectoderm and mesoderm, generally thought to be a fundamental division in all organisms, was incomplete. When the precise cell lineage was determined, founder cells thought to produce only ectodermal or mesodermal cell types were found to produce both. In fact, cells capable of generating both ectodermal and mesodermal descendants arise late in embryogenesis: a few divide to produce a muscle cell and a neuron. This observation demonstrates that the ectoderm/mesoderm decision need not precede other decisions. Because the number of distinguishable cell types in the animal is large compared to the number of cells, many divisions create non-equivalent daughters, and thus qualify as developmental decision points. However, the patterns that arise in the lineage suggest that at least four developmental strategies are utilized (see Fig. 1). The first recurrent pattern is the appearance of precursors that produce clones of a single cell type. Examples of such precursors are the gut and germ founder cells mentioned above, and another founder cell that generates 20 body muscle cells. Later, a cell arises that makes 8 hypodermal (skin) cells. More than 40 additional cells produce identical daughters. One way to interpret this pattern is that a switch that determines the fate of a cell can be followed by a simple proliferation. In contrast, a second recurrent theme is a precursor cell that produces all the cells of a functional unit composed of different cell types. Each arm of the symmetrical twoarmed gonad is generated by one of two equivalent precursors. Each of the 18 'ray' sensilla in the male arises clonally. However, it is worth noting that some structures have surprisingly diverse origins; for example none of the cell types present in the pharynx (esophagus) is contributed by a single precursor. Elsewhere, similar structures may have clonal or non-clonal origins. For example, a sensillum called the deifid is built from unrelated ceils while the

TIBS - October 1983 similar postdeirid is formed from the descendants of a single precursor. A third recurrent theme is the production of stem cells that divide repeatedly, each time producing a differentiated daughter. This mode of development is most apparent in the lateral hypodermis. Here a set of cells divides repeatedly, each time producing a differentiated hypodermal cell or neuroblast (cell that produces neurons) plus another stem cell. Although many of the lineages do not obviously involve stem cells, evidence for the existence of underlying stem cell programs comes from the mutant unc-86, in which a loss or reduction in the function of a gene converts certain neuroblasts into typical stem cells7. A fourth, rather unexpected, theme is that many developmental sequences are apparently modular, and can be implemented at multiple positions in the lineage. For example, similar sublineages produce the ventral cord motoneurons, the sensory rays and many of the sensory structures in the head. The stem cells in the lateral hypodermis, mentioned above, produce similar sublineages. In certain instances, duplication may have preceded subsequent evolutionary diversification: for example, some but not all of the lateral hypodermal stem cells generate neuroblasts. The ability to insert identical developmental sequences at apparently arbitrary lineal positions is nowhere as striking as in the generation of left/right symmetry during embryogenesis. One might expect that bilateral homologues would be produced by a set of left-right divisions early in development. However homologues often arise simultaneously, but at apparently unrelated lineal positions. To understand development we need to learn how decisions that can create clonal precursors, stem cells, and recurrent sublineages are controlled. By destroying cells with a laser microbeam, it is possible to ask whether the decision to follow a certain developmental pathway is made in response to external cues, or whether the instructions are inherited. Specific cells have been killed with a laser microbeam and the fates of the remaining cells determined 1.s.9.10. Although certain cell fates are indeed controlled by cell-cell interactions, the great majority do not seem to depend upon communication with neighbors. This suggests that many cells know who they are because of their lineage. Perhaps the most attractive hypothesis for the control of these autonomous lineages is that a switch within a cell is itself controlled by a switch thrown in the parent, and so on, back to the first cleavages of the egg. Evidence for many of the switches sug-

351 gested by the lineage has been obtained from homeotic mutations that convert the fates of cells (and their descendants) into those of cells found elsewhere in the animal (Refs 7, 11, 12, 13; Kenyon and Hedgecock, unpublished results; Ambros and Horvitz, personal communication). In these mutants, cell fates that would normally differ are the same. These mutations thus identify genes that may function to create cell diversity during development. A molecular analysis of these genes and their products may eventually tell us how the switches operate. References l Sulston, J. E., Schierenberg, E., White, J. G. and Thomson, J. N. (1983)Develop. Biol. (in press) 2 Sulston, J. E. and Horvitz, H. R. (1977)Develop. Biol. 56, 110-156 3 Kimble, J. and Hirsh, D. (1979) Develop. Biol. 70, 396-417

4 Sternberg, P. W. and Horvitz, H. R. (1982) Develop. Biol. 93,181-205 5 Sulston, J. E. (1983) in Cold Spring Harbor Symposium 48, (in press) 6 yon Ehrenstein, G. and Schierenberg, E. (1980) in Nematodes as Biological Models, Vol. I (Zuckerman, B. M., ed.), pp. 2-71, Academic Press, London 7 Chalfie, M., Horvitz, H. R. and Sulston, J. E. ( 1981 ) Cell 24, 59-69 8 Kimble, J. (1981)Develop. Biol. 87,286-300 9 Kimble, J. E. and White, J. G. (1981) Develop. Biol. 81,208-219 10 Sulston, J. E. and White, J. G. (1980) Develop. Biol. 78,577-597 11 Horvitz, H. R., Sternberg, P. W., Greenwald I. S., Fixsen, W. and Moyed Ellis, H. (1983) in Cold Spring Harbor Symposium 48 (in press) 12 Greenwald, 1. S., Sternberg, P. W. and Horvitz, H. R. (1983)Develop. Biol. (in press) 13 Hodgkin, J. (1980) Genetics 96,649-664 CYNTHIA J. KENYON MRC Laboratory of Molecular Biology, Hills Road, Cambridge, UK.

Polymath Potassius Clay A Harlequinonesque Tale by Horst Ibelgaufts Potassius Clay stemmed from an old family of clergymen. A long time ago, when his father had forced him to choose between 'Publish or Parish', he had decided upon the former. 'EM, so be it', his father had said grudgingly. Now, Potassius Clay was mainly known as the editor of the Plus Strand Magazine, the co-author of a highly succinessful textbook on electronic spinster resonance, and the author of a pioneering, profound philosophical treatise about paragoges in genetic languages. Being an amateur zoologist and discoverer of Lipidoptera gallopans Clayi, Potassius Clay had written a book for the uninitiated cryptozoologist called How to

discover scientifically undescribed animal species without really trying. However, he had also been highly productive in fiction. Two books, The Reading

Framely Parsonage, and The Calcium Gates to Heaven, written under his nom de plume, Ali Kwott, had hit the top-tenbestseller list. Clay was a Fellow of the Royal Society for Decibel Ringing, corresponding member of the League Against Nuclear and Cytoplasmic Armament, Fellow of the Royal College of Surrogate Geneticists, and Chairman of the Royal Society for the Prevention of Cruelty to Monoclonal AniHorst Ibelgaufts is at Chemisches Laboratorium der Universitiit MYmchen, lnstitut flit Biochemie, Karlstrasse 23 8 Miinchen 2, FRG.

mals. Needless to say, he had retained a mystic relationship towards bat, ball, and bile, and he was a well-respected, active member of the Royal Pol(1)o Club. It is less known, however, that P.C. had been prospecting successfully in Clonedike County in his early days, and had later increased his already camphortable fortune by selling pharmasuitical endocrinolines. He had also invented and marketed Eurokinase ~, before starting a third career as a highly respected ornithinologist. P.C. also owned two off-double-bondstreet pubs (The Boat and Chair and Ye Olde Pestle and Mortar). In one word: Potassius Clay was a wealthy versatile, almost harlequinonesque man, a polymath. The other night, Potassius was on his way back home from Chromaffin Bay (corticotropic of Cancer), where he had stayed to recover from severe jaundice, an affliction which he had treated particularly disdanely in its initial stages. He loved the parochirality of Chromaftin Bay County freontically, especially the ubiquitous lovely gardens full of bougainvilli, conAfers, and poisson i.V.

P.C. had just been listeningto his favourite tunes from a tape cassette ('Tweeny Todd the Barber', 'House of the Ricin Sun', 'Micelle, my Belle', and 'Rule Brijtannia' ), when his old car, a 1922 Austin Pili, stopped dead at a gap junction. Potassius got tricyclically depressed, his complex ion became a pale mauve, and he grinned antimetabolitically. He knew that the attack

1983, ElsevierScience PublishersB.V., Amsterdam 0376- 5067/83/$01.00