Models for pattern formation in imaginal discs

Imaginal Discs: The Genetic and Cellular Logic of Pattern Formation
by Lewis I. Held, Jr.

The following models have played an important role in the history of research on disc patterning. Names for some of the models (*) were coined for convenience.

Border Guard Model*: Like the Selector Affinity Model that preceded it, this model attempts to explain why the A/P compartment boundary (and others like it) is so straight (Blair and Ralston, 1997; Hidalgo, 1998). Unlike its predecessor, however, this model invokes homophilic affinities only for cells at the interfaces between compartments, not within the compartments themselves. At the A/P boundary, any cell that receives the Hedgehog signal from nearby P cells will turn ON its decapentaplegic gene and adopt an affinity that causes it to adhere to other border cells. Hence, any raggedness in the border zone will be "ironed out", and the line will straighten. Intermixing of A and P cells is prevented not by any sort of A vs. P affinity, but rather by the interposition of this file of "border guard" cells. This notion of a third state emerging at the interface between two others is an old one in embryology (Stern, 1936; Weiss, 1961), and it helps explain how patterns can automatically become more elaborate.

Boundary Model: Hans Meinhardt proposed this model in 1980 (Meinhardt, 1980) as an alternative to the Polar Coordinate Model, and he revised it in 1983 (Meinhardt, 1983). Its main tenets proved correct (Campbell and Tomlinson, 1995): (1) contact between compartments elicits a morphogen at the interface and (2) the intersection of those boundaries defines the appendage tip as a "distal organizer". However, the model envisioned three long-range morphogens, whereas in fact there are only two (Dpp and Wingless).

Combinatorial Cascade Model*: This model was proposed by Donald Ready et al. in 1986 (Ready et al., 1986) and refined by other authors (Cagan and Ready, 1989; Tomlinson and Ready, 1987). Like the Crystallization Model, which it supplanted, this model explains intra-ommatidial patterning in terms of sequential induction. NaĆve cells are assumed to adopt fates based on information they receive from adjacent neighbors. For example, a naĆve cell that comes into contact with R1, R6, and R8, would "know" to become an R7 photoreceptor due to the combination of (inductive) signals that it receives from those cells. Unlike the Crystallization Model, there is no propagation of signals beyond the ommatidium. To wit, some other mechanism (e.g., Inhibitory Field and Wavefront) must site ommatidial founder cells (like planting seeds in the eye field), whereupon a cascade elicits shells of newly specified cells around each founder (like a seed "growing" into an ommatidium).

Crystallization Model: This 1976 model was the first attempt to explain how the hexagonal lattice of ommatidia is created. Ready, Hanson, and Benzer argued that as the morphogenetic furrow sweeps across the eye epithelium from posterior to anterior, all newborn cells adopt fates based on the identities of their posterior neighbors (Ready et al., 1976). Thus, the lattice should build on itself in the same way that a crystal accretes around a seed crystal. However, in certain mutants where ommatidia are sparse, individual ommatidia can develop in isolation (Baker and Rubin, 1989). This ability of cells to adopt correct fates despite being far from any obvious "template" contradicted this model, which was abandoned in favor of the Combinatorial Casdade Model. The latter model also invokes a template-like process of fate assignment, but only within ommatidia (not between them).

Gradient of Developmental Capacity Model: This model was devised by Peter Bryant in 1971 (Bryant, 1971; Bryant, 1974) to explain why certain fragments of discs regenerate while the reciprocal pieces duplicate. It asserted that (1) the ability to regenerate is graded within each disc and (2) new cells born at a wound edge must adopt fates that are lower in the gradient. Thus, if a disc is spanned by a gradient "654321" (with a slash marking the cut edge and underlining denoting new growth), then bisection creates two pieces, both of which grow "downhill": the "654/" piece regenerates (654/321) while the "/321" piece duplicates (123/321). The model was abandoned in favor of the Polar Coordinate Model when the behavior of a wound edge was found to depend not only on its own level but also on the edges that it contacts (French et al., 1976).

Inhibitory Field and Wavefront Model*: Originally devised by Donald Ede as an explanation for hexaogonal lattices of feathers in birds (Ede, 1972), this model was applied to the hexagonal lattice of ommatidia in fly eyes by Renfranz and Benzer in 1989 (Renfranz and Benzer, 1989) and Baker et al. in 1990 (Baker et al., 1990). Cells are supposedly unable to make ommatidia until the morphogenetic furrow (wavefront) reaches them, whereupon any cell that becomes an ommatidial founder (R8 precursor) emits a diffusible inhibitor. No cell within the range of any other cell's inhibitory field can become a founder. These rules ensure that each new column of founders will arise in the crevices of the previous column's inhibitory fields-thus forcing the pattern into a hexagonal lattice.

Polar Coordinate (PC) Model: Vernon French, Peter Bryant, and Susan Bryant proposed this model in 1976 (French et al., 1976) and revised it in 1981 (Bryant et al., 1981). The model synthesized data on regeneration in cockroach legs, fly discs, and amphibian limbs, and it was the first hint that arthropods and chordates use similar rules for appendage outgrowth. Each cell's position was supposed to be specified as (1) a radius and (2) a declination. This "clockface" model differed from earlier ideas in its reliance on signaling between adjacent cells, rather than on morphogens. Its popularity waned as morphogens were documented (Campbell et al., 1993), and it was overturned when regeneration was found to rely on the peripodial membrane (Gibson and Schubiger, 1999), rather than on intra-epithelial contacts that were essential to the model.

Positional Information Hypothesis: This way of thinking was proposed by Lewis Wolpert in 1969 (Wolpert, 1969), and it has remained the dominant paradigm for pattern formation ever since (Wolpert, 1996). The premise is that cells are "informed" about their positions within coordinate systems that span developing organs ("fields"). Positional information ("PI") is supposed to be encoded in the concentration of a molecule ("morphogen") that is secreted at certain reference points or axes. Diffusion of morphogen creates "gradients" that are usually depicted as linear but are likely exponential. Indeed, patterning in leg and wing discs is controlled by gradients of Hh, Dpp, and Wg (Lecuit et al., 1996; Nellen et al., 1996; Strigini and Cohen, 1997; Tanimoto et al., 2000; Zecca et al., 1996). How PI is processed is disputed (Gurdon and Bourillot, 2001). Wolpert argued that every cell records its morphogen level as a "positional value" and later translates this quantitative value into a qualitative state of differentiation. However, the evidence from discs argues otherwise: only a few levels of each gradient appear to turn target genes ON or OFF-e.g., omb and spalt in the wing (Nellen et al., 1996).

Prepattern Hypothesis: Curt Stern invented the concept of prepatterns in 1954 (Stern, 1954), and it served as the paradigm for disc patterning until 1969 when it was supplanted by the idea of positional information (Tokunaga, 1978; Wolpert, 1989). Patterns of structures were assumed to be preceded by prepatterns of "singularities"-qualitative signals that induce pattern elements. For a cell to respond to the signal at its site, it must be "competent" to receive and transduce the signal. The model was revived in 1980 (NĹsslein-Volhard and Wieschaus, 1980), when the segmentation gene hierarchy was found to involve a cascade of localized signals. The best example of how the model applies is the prepattern of bristle-inducing transcription factors in the developing notum (Modolell and Campuzano, 1998; Sato et al., 1999; Simpson, 1996; Tomoyasu et al., 1998).

Selector Affinity Model: This model, advocated by Gines Morata and Peter Lawrence in 1975 (Lawrence and Morata, 1976; Morata and Lawrence, 1975) is a corollary of the Selector Gene Model. The idea is that cells expressing different selector genes exhibit different affinities. For example, consider the anterior (A) vs. posterior (P) compartments of the wing disc. P cells express the selector gene engrailed, while A cells do not. Hence, P cells should adhere more strongly to other P cells than to A cells, and vice versa-perhaps due to a cadherin gene controlled by engrailed (Pradel and White, 1998). The straightness of the A/P boundary would follow as a natural consequence. However, other explanations exist for the straightness of that line-e.g., the Border Guard Model.

Selector Gene Model: Antonio Garc√a-Bellido offered this model in 1975 (Garc√a-Bellido, 1975). Extending Stuart Kauffman's notion of binary codes (Kauffman, 1973), Garc√a-Bellido argued that the ON/OFF states of certain genes identify definite regions of the body. These executive ("selector") genes control downstream ("realizator") genes that implement histotypes. Selector genes indeed exist (Guss et al., 2001; Lawrence and Struhl, 1996; Pradel and White, 1998; Tautz, 1996), and mutations in them cause homeosis (Lawrence and Struhl, 1996). Most of these genes belong to the homeobox family (Affolter and Mann, 2001; Brewster et al., 2001; Cavodeassi et al., 2000; Weatherbee and Carroll, 1999).

Stop the Clock! Model*: Like the Crystallization and Combinatorial Cascade Models that preceded it, this model aims to explain intra-ommatidial patterning. It was devised by Matthew Freeman in 1997 (Freeman, 1997). The basic idea is that all cells within a nascent ommatidium progress synchronously through a series of transcription factors, like a minute hand on a clock. When a cell receives a "Stop!" signal from any neighbor, the cell stops the progression and retains its state. The "Stop!" signal is received by Egfr. [Tom Brody and Ward Odenwald found a similar device for CNS neuroblasts (Brody and Odenwald, 2000) where "Stop!" depends on mitosis.] The following cascade of "Stop!" signals is conjectural ("p" denotes "precursor"): R8p ' R2/5p ' R3/4p ' R1/6p; then R8p (late signal) ' R7p; and finally, all R cells (?) ' cone cells ' PPCs ' SPCs ' TPCs.

References

Affolter, M. and Mann, R. (2001). Legs, eyes, or wings--selectors and signals make the difference. Science 292, 1080-1081. Medline abstract: 11352058

Baker, N. E., Mlodzik, M. and Rubin, G. M. (1990). Spacing differentiation in the developing Drosophila eye: a fibrinogen-related lateral inhibitor encoded by scabrous. Science 250, 1370-1377. Medline abstract: 2175046

Baker, N. E. and Rubin, G. M. (1989). Ellipse mutations in the Drosophila homologue of the EGF receptor affect pattern formation, cell division, and cell death in eye imaginal discs. Dev. Biol. 150, 381-396. Medline abstract: 1551482

Blair, S. S. and Ralston, A. (1997). Smoothened-mediated Hedgehog signalling is required for the maintenance of the anterior-posterior lineage restriction in the developing wing of Drosophila. Development 124, 4053-4063. Medline abstract: 9374402

Brewster, R., Hardiman, K., Deo, M., Khan, S. and Bodmer, R. (2001). The selector gene cut represses a neural cell fate that is specified independently of the Achaete-Scute-Complex and atonal. Mechs. Dev. 105, 57-68. Medline abstract: 11429282

Brody, T. and Odenwald, W. F. (2000). Programmed transformations in neuroblast gene expression during Drosophila CNS lineage development. Dev. Biol. 226, 34-44. Medline abstract: 10993672

Bryant, P. J. (1971). Regeneration and duplication following operations in situ on the imaginal discs of Drosophila melanogaster. Dev. Biol. 26, 637-651.

Bryant, P. J. (1974). Determination and pattern formation in the imaginal discs of Drosophila. Curr. Top. Dev. Biol. 8, 41-80.

Bryant, S. V., Bryant, P. J. and French, V. (1981). Distal regeneration and symmetry. Science 212, 993-1002.

Cagan, R. L. and Ready, D. F. (1989). The emergence of order in the Drosophila pupal retina. Dev. Biol. 136, 346-362.

Campbell, G. and Tomlinson, A. (1995). Initiation of the proximodistal axis in insect legs. Development 121, 619-628.

Campbell, G., Weaver, T. and Tomlinson, A. (1993). Axis specification in the developing Drosophila appendage: the role of wingless, decapentaplegic, and the homeobox gene aristaless. Cell 74, 1113-1123. Medline abstract: 8104704

Cavodeassi, F., Modolell, J. and Campuzano, S. (2000). The Iroquois homeobox genes function as dorsal selectors in the Drosophila head. Development 127, 1921-1929. Medline abstract: 10751180

Ede, D. A. (1972). Cell behaviour and embryonic development. Internat. J. Neurosci. 3, 165-174.

Freeman, M. (1997). Cell determination strategies in the Drosophila eye. Development 124, 261-270. Medline abstract: 9053303

French, V., Bryant, P. J. and Bryant, S. V. (1976). Pattern regulation in epimorphic fields. Science 193, 969-981.

García-Bellido, A. (1975). Genetic control of wing disc development in Drosophila. In Cell Patterning, vol. 29 (ed. R. Porter and J. Rivers), pp. 161-182. Amsterdam: Elsevier.

Gibson, M. C. and Schubiger, G. (1999). Hedgehog is required for activation of engrailed during regeneration of fragmented Drosophila imaginal discs. Development 126, 1591-1599. Medline abstract: 10079222

Gurdon, J. B. and Bourillot, P.-Y. (2001). Morphogen gradient interpretation. Nature 413, 797-803. Medline abstract: 11677596

Guss, K. A., Nelson, C. E., Hudson, A., Kraus, M. E. and Carroll, S. B. (2001). Control of a genetic regulatory network by a selector gene. Science 292, 1164-1167. Medline abstract: 11303087

Hidalgo, A. (1998). Growth and patterning from the engrailed interface. Int. J. Dev. Biol. 42, 317-324. Medline abstract: 9654015

Kauffman, S. A. (1973). Control circuits for determination and transdetermination. Science 181, 310-318.

Lawrence, P. A. and Morata, G. (1976). Compartments in the wing of Drosophila: A study of the engrailed gene. Dev. Biol. 50, 321-337.

Lawrence, P. A. and Struhl, G. (1996). Morphogens, compartments, and pattern: lessons from Drosophila? Cell 85, 951-961. Medline abstract: 8674123

Lecuit, T., Brook, W. J., Ng, M., Calleja, M., Sun, H. and Cohen, S. M. (1996). Two distinct mechanisms for long-range patterning by Decapentaplegic in the Drosophila wing. Nature 381, 387-393. Medline abstract: 8632795

Meinhardt, H. (1980). Cooperation of compartments for the generation of positional information. Z. Naturforsh. 35c, 1086-1091.

Meinhardt, H. (1983). Cell determination boundaries as organizing regions for secondary embryonic fields. Dev. Biol. 96, 375-385.

Modolell, J. and Campuzano, S. (1998). The achaete-scute complex as an integrating device. Int. J. Dev. Biol. 42, 275-282. Medline abstract: 9654009

Morata, G. and Lawrence, P. A. (1975). Control of compartment development by the engrailed gene in Drosophila. Nature 255, 614-617.

Nellen, D., Burke, R., Struhl, G. and Basler, K. (1996). Direct and long-range action of a DPP morphogen gradient. Cell 85, 357-368. Medline abstract: 8616891

Nüsslein-Volhard, C. and Wieschaus, E. (1980). Mutations affecting segment number and polarity in Drosophila. Nature 287, 795-801.

Pradel, J. and White, R. A. H. (1998). From selectors to realizators. Int. J. Dev. Biol. 42, 417-421. Medline abstract: 9654026

Ready, D. F., Hanson, T. E. and Benzer, S. (1976). Development of the Drosophila retina, a neurocrystalline lattice. Dev. Biol. 53, 217-240.

Ready, D. F., Tomlinson, A. and Lebovitz, R. M. (1986). Building an ommatidium: geometry and genes. In Development of Order in the Visual System, (ed. S. R. Hilfer and J. B. Sheffield), pp. 97-125. Berlin: Springer-Verlag.

Renfranz, P. J. and Benzer, S. (1989). Monoclonal antibody probes discriminate early and late mutant defects in development of the Drosophila retina. Dev. Biol. 136, 411-429. Medline abstract: 2511049

Sato, M., Kojima, T., Michiue, T. and Saigo, K. (1999). Bar homeobox genes are latitudinal prepattern genes in the developing Drosophila notum whose expression is regulated by the concerted functions of decapentaplegic and wingless. Development 126, 1457-1466. Medline abstract: 10068639

Simpson, P. (1996). Drosophila development: A prepattern for sensory organs. Curr. Biol. 6, 948-950. Medline abstract: 8805323

Stern, C. (1936). Genetics and ontogeny. Am. Nat. 70, 29-35.

Stern, C. (1954). Two or three bristles. Am. Sci. 42, 213-247.

Strigini, M. and Cohen, S. M. (1997). A Hedgehog activity gradient contributes to AP axial patterning of the Drosophila wing. Development 124, 4697-4705. Medline abstract: 9409685

Tanimoto, H., Itoh, S., ten Dijke, P. and Tabata, T. (2000). Hedgehog creates a gradient of DPP activity in Drosophila wing imaginal discs. Molec. Cell 5, 59-71. Medline abstract: 10678169

Tautz, D. (1996). Selector genes, polymorphisms, and evolution. Science 271, 160-161. Medline abstract: 8539613

Tokunaga, C. (1978). Genetic mosaic studies of pattern formation in Drosophila melanogaster, with special reference to the prepattern hypothesis. In Genetic Mosaics and Cell Differentiation, (ed. W. J. Gehring), pp. 157-204. Berlin: Springer-Verlag.

Tomlinson, A. and Ready, D. F. (1987). Neuronal differentiation in the Drosophila ommatidium. Dev. Biol. 120, 366-376.

Tomoyasu, Y., Nakamura, M. and Ueno, N. (1998). Role of Dpp signalling in prepattern formation of the dorsocentral mechanosensory organ in Drosophila melanogaster. Development 125, 4215-4224. Medline abstract: 9753676

Weatherbee, S. D. and Carroll, S. B. (1999). Selector genes and limb identity in arthropods and vertebrates. Cell 97, 283-286. Medline abstract: 10319808

Weiss, P. (1961). From cell to molecule. In The Molecular Control of Cellular Activity, (ed. J. M. Allen), pp. 1-72 (reprinted in Weiss's 1968 book). New York: McGraw-Hill.

Wolpert, L. (1969). Positional information and the spatial pattern of cellular differentiation. J. Theor. Biol. 25, 1-47.

Wolpert, L. (1989). Positional information and prepattern in the development of pattern. In Cell to Cell Signalling: From Experiments to Theoretical Models, (ed. A. Goldbeter), pp. 133-143. New York: Acad. Pr.

Wolpert, L. (1996). One hundred years of positional information. Trends Genet. 12, 359-364.

Zecca, M., Basler, K. and Struhl, G. (1996). Direct and long-range action of a Wingless morphogen gradient. Cell 87, 833-844. Medline abstract: 8855666 For further references, see the unabridged bibliography also posted on this website.

Imaginal Discs Index


Home page: The Interactive Fly © 1995, 1996 Thomas B. Brody, Ph.D.

The Interactive Fly resides on the
Society for Developmental Biology's Web server.