Physico-Genetic Determinants in the Evolution of Development Stuart A. Newman Science 338, 217 (2012); DOI: 10.1126/science.

1222003

This copy is for your personal, non-commercial use only.

Permission to republish or repurpose articles or portions of articles can be obtained by following the guidelines here. The following resources related to this article are available online at www.sciencemag.org (this information is current as of January 15, 2013 ): Updated information and services, including high-resolution figures, can be found in the online version of this article at: http://www.sciencemag.org/content/338/6104/217.full.html Supporting Online Material can be found at: http://www.sciencemag.org/content/suppl/2012/10/10/338.6104.217.DC1.html A list of selected additional articles on the Science Web sites related to this article can be found at: http://www.sciencemag.org/content/338/6104/217.full.html#related This article cites 27 articles, 9 of which can be accessed free: http://www.sciencemag.org/content/338/6104/217.full.html#ref-list-1 This article appears in the following subject collections: Evolution http://www.sciencemag.org/cgi/collection/evolution

Science (print ISSN 0036-8075; online ISSN 1095-9203) is published weekly, except the last week in December, by the American Association for the Advancement of Science, 1200 New York Avenue NW, Washington, DC 20005. Copyright 2012 by the American Association for the Advancement of Science; all rights reserved. The title Science is a registered trademark of AAAS.

Downloaded from www.sciencemag.org on January 15, 2013

If you wish to distribute this article to others, you can order high-quality copies for your colleagues, clients, or customers by clicking here.

SPECIALSECTION
a niche (11). Theoretical models that include both cell-cell communication and intracellular expression dynamics have been investigated (12, 13). Extensive simulations of such models over a huge variety of gene expression networks have found that cells that can both proliferate and also differentiate to cell types of different composition generally show temporal oscillations in their gene expressions at the single-cell level (Fig. 2B). In such cases, with the increase in cell number, state differences between cells are amplified by cell-cell communication such that the sensitivity to a signal increases. Some cells at a certain phase of oscillations (i.e., at a certain location within the orange trajectory in Fig. 2B) escape their original attractor in response to a signal and fall into the trough of a different attractor, whereas other cells of different phases remain with the original attractor. Thus, gene expression oscillations are necessary for stemness, potentiality both to proliferate and differentiate, whereas the loss of stemness is characterized by a loss of oscillatory dynamics. Notably, in this mechanism, the timing and pathway of differentiation are robust to noise, a property Waddington termed homeorhesis (1). With cellcell communication, the differentiation frequency of a stem cell is autonomously regulated by the population of each cell type, resulting in a robust population ratio. Recently, Huang used time-series transcriptome data to experimentally verify the existence of attractors in the dynamics of hematopoietic progenitor cells by demonstrating the robustness of the cellular state (14). Additionally, from the fluctuating expression level of stem cell marker Sca1, they found slow-scale changes in cellular states, which was suggested to be regulated by cell-cell communication (15). Single-cell measurements of gene expression dynamics have shown heterologous gene expressions of Rex1, Nanog, and Stella in embryonic stem cell populations (16) and Sca1 in hematopoietic stem cells (15, 17), a heterogeneity closely linked to the fate of the stem cell. One possible mechanism for such heterogeneity could be noise in the expression dynamics. Another is oscillatory expression dynamics. Indeed, Kageyama and colleagues found temporal oscillations in the Hes1 expression level of neural precursors and embryonic stem cells, where the phase of the oscillation was potentially seen to control the fate decision (18, 19), whereas existence of a complex dynamic attractor is also suggested (20). Furthermore, cell-cell communication via Notch-Delta signaling was suggested to regulate the fate decision of neural progenitors under the control of the oscillatory expression dynamics of Hes1 and other genes (18). Using a dynamical-systems approach to explain the differentiation of stem cells, we have described here how fluctuating and oscillatory gene expressions underlie the essence of stemness. If so, reactivating specific genes may recover these oscillations in differentiated cells to potentially restore potency (21). To characterize the attractors of stem and differentiated cells quantitatively, however, further experiments, including systematic sensitivity analysis of gene expressions (22), as well as theoretical formulations that go beyond Waddington's epigenetic landscape, are needed.
References
1. C. H. Waddington, The Strategy of the Genes (George Allen & Unwin, London, 1957). 2. J. Wang, K. Zhang, L. Xu, E. Wang, Proc. Natl. Acad. Sci. U.S.A. 108, 8257 (2011). 3. S. Huang, Bioessays 34, 149 (2012). 4. P. W. Andrews, Philos. Trans. R. Soc. Lond. 357, 405 (2002). 5. J. M. Slack, Nat. Rev. Genet. 3, 889 (2002). 6. S. H. Strogatz, Nonlinear Dynamics and Chaos (Westview, Baolder, CO, 2001). 7. S. A. Kauffman, The Origins of Order: Self-Organization and Selection in Evolution (Oxford Univ. Press, Oxford, 1993). 8. G. Forgacs, S. A. Newman, Biological Physics of The Developing Embryo (Cambridge Univ. Press, Cambridge, 2006). 9. S. Huang, Bioessays 31, 546 (2009). 10. R. Serra, M. Villani, A. Barbieri, S. A. Kauffman, A. Colacci, J. Theor. Biol. 265, 185 (2010). 11. D. C. Kirouac et al., Mol. Syst. Biol. 6, 417 (2010). 12. C. Furusawa, K. Kaneko, J. Theor. Biol. 209, 395 (2001). 13. N. Suzuki, C. Furusawa, K. Kaneko, PLoS ONE 6, e27232 (2011). 14. S. Huang, G. Eichler, Y. Bar-Yam, D. E. Ingber, Phys. Rev. Lett. 94, 128701 (2005). 15. H. H. Chang, M. Hemberg, M. Barahona, D. E. Ingber, S. Huang, Nature 453, 544 (2008). 16. T. Graf, M. Stadtfeld, Cell Stem Cell 3, 480 (2008). 17. C. Pina et al., Nat. Cell Biol. 14, 287 (2012). 18. H. Shimojo, T. Ohtsuka, R. Kageyama, Neuron 58, 52 (2008). 19. T. Kobayashi et al., Genes Dev. 23, 1870 (2009). 20. M. A. Canham, A. A. Sharov, M. S. Ko, J. M. Brickman, PLoS Biol. 8, e1000379 (2010). 21. K. Takahashi, S. Yamanaka, Cell 126, 663 (2006). 22. A. Nishiyama et al., Cell Stem Cell 5, 420 (2009). 10.1126/science.1224311

PERSPECTIVE

Physico-Genetic Determinants in the Evolution of Development

Stuart A. Newman Animal bodies and the embryos that generate them exhibit an assortment of stereotypic morphological motifs that first appeared more than half a billion years ago. During development, cells arrange themselves into tissues with interior cavities and multiple layers with immiscible boundaries, containing patterned arrangements of cell types. These tissues go on to elongate, fold, segment, and form appendages. Their motifs are similar to the outcomes of physical processes generic to condensed, chemically excitable, viscoelastic materials, although the embryonic mechanisms that generate them are typically much more complex. I propose that the origins of animal development lay in the mobilization of physical organizational effects that resulted when certain gene products of single-celled ancestors came to operate on the spatial scale of multicellular aggregates. any of the classic phenomena of early animal developmentthe formation and folding of distinct germ layers during gastrulation, the convergence and extension movements leading to embryo elongation,

the formation of somites (paired blocks of tissue) along the main axis of vertebrate embryos, the generation of the vertebrate limb skeleton, the arrangement of feathers and hairshave been productively analyzed by mathematical and comSCIENCE VOL 338

putational models that treat morphological motifs as expected outcomes of physical process that are generic; i.e., pertaining as well to certain nonliving, chemically active, viscoelastic materials (14). Given that the thousands of genes of extant animals have been subject to mutation and (at the organismal level) natural selection over the more than 600 million years since the Metazoa first emerged (5), it is counterintuitive but revealing that the morphological motifs animals began with were carried over to the present, with few additions. Many developmental events that might be characterized by their simple generic physical properties are, in fact, much more complex. For example, many cells of embryonic tissues are individually mobile while, at the same time, collectively cohesive, as in the formation of distinct layers during gastrulation and of boundaries during later development: behaviors that had been attributed to cell adhesive differentials, with analogy to the phase separation of liquids such as oil and water (1). Although differential adhesion is indeed capable of sorting cells into separate
Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY 10595, USA. E-mail: [email protected]

www.sciencemag.org

12 OCTOBER 2012

217

Downloaded from www.sciencemag.org on January 15, 2013

Forces in Development
The operation of generic physical effects in before being recruited into developmental roles layers, the embryo is more complicated; for example, with tension being exerted on the cell animal embryogenesis, along with developmen- as multicellularity emerged (23, 24). The morphogenetic and patterning functionalsurface by the cytoskeleton and active cell-cell tal mechanisms that are complex and nongeneric repulsion (phenomena with no known counter- but nonetheless produce similar stereotypical mor- ities that arose when interaction tool kit molecules, parts in liquids), often contributing more to the phological motifs (multiple layers, interior cav- acting in the new multicellular context, mobilized configuration of the separated tissues than rel- ities, segments, folds, etc.), suggest a scenario in generic physical effects, have been termed dywhich the nongeneric mechanisms are evolved namical patterning modules (DPMs) (22). Although ative affinities (6) More generally, cells in embryos have the embellishments of the generic ones, with selec- primitive metazoan-type body plans could have ability, via contractile and protrusive activities, to tion stabilizing and reinforcing inherent forms quickly arisen in aggregates of genetically variaexert forces on one another and on the extracel- rather than inventing new ones (20). Hierarchical ble cells as long as they contained DPM-enabling lular matrices they produce (7). Although these programs of gene expression during the devel- genes (Fig. 1, aggregation route), without enforced mechanical properties can lead to, and in some opment of modern animals (21) regulate shape genetic uniformity among the cells of multicellular cases account for, the buckling of epithelial tissues and form by coordinating, fine-tuning, and con- forms, intraorganismal competition would tend to into ridges, as in neurulation, this developmental straining the activities of a subset of the con- undermine their persistence (25). The emergence process actually occurs by several different mech- served developmental tool kit, the tools of of an egg stage of development, with the cell clusanisms across chordates, only some of which de- which are the products of genes that directly ter stage of development then generated by cell mediate cell-cell interactions (22). These mole- cleavage, would have obviated such chimerism pend on mechanically mediated buckling (8). An embryos cells are tiny chemical reactors cules (such as cadherins, Notch, Wnt, Hedgehog, (Fig. 1, cleavage route), facilitating the generawith stored and exchangeable sources of en- bone morphogenetic protein, and collagens) typ- tion of evolutionarily stable lineages (26) (Fig. 1). The early products of DPMs would have ergy. This is evidenced in their ability to switch ically served single-cell functions in one or more among multiple stable compositional states (the unicellular ancestors of the multicellular animals borne the generic morphological signatures of basis for cell differentiation) (1, 9) and to exhibit biochemical oscillations (the basis of the cell cycle Non-stable lineages and other cell-physiological perioStable lineages S dicities) (10, 11). By virtue of this dynamicity, embryonic tissues are chemically excitable media, the physical properties of which can explain some enigmatic developmenCleavage Aggregation Gallus tal phenomena. Nonliving chemical embryo oscillators that are weakly coupled Dendraster readily come into synchrony (12). larva Correspondingly, interactions between adjoining cells in an embryonic tissue will synchronize intracellular oscillations; an example is the periodic expression of the transcriptional modulator Hes1 transforming Drosophila a clump of individual cells into a embryo Trichoplax globally coordinated embryonic field (13). Although a spatial uniformity of biochemical state can thus emerge in embryonic tissues, patterns can also form based on the self-organizing capabilities of inCaenorhabditis teracting diffusible activators and Mnemiopsis embryo inhibitors of cell differentiation (morphogens) (1416), Some periodic and quasiperiodic develLoligo embryo Amphimedon opmental patterns (such as the distribution of hairs, pigment patches, Fig. 1. A core set of physico-genetic modules underlies the morphological evolution of animals. Multicellular entities or skeletal structures) clearly de(center image) were formed by the aggregation of unicellular organisms (red curved arrow) or the cleavage of enlaged pend on such effects (17), but oth- cells [proto-eggs (26) or eventually fertilized eggs] (green curved arrow). The green inner circle shows morphological ers, such as the seven stripes of motifs generated by some of the key DPMs: physical forces and effects relevant to the multicellular scale, mobilized by pair-rule proteins in the syncytial certain ancient single-cell gene products and pathways. Emergent motifs include (clockwise from top of inner circle) Drosophila embryo, although they appendages, segments, elongated bodies and primordia, coexisting alternative cell types, interior cavities, dispersed cells, exhibit some self-organizing as- and multiple layers. Genetically uniform clusters produced stable lineages (straight green arrows), whereas chimeric pects (18), are generated in a less clusters did not (broken red arrows). Contemporary organisms containing some or all of these motifs are shown in the outer generic fashion, employing stripe- circle. Clockwise from top right: vertebrate (Gallus) embryo, arthropod (Drosophila) embryo, ctenophore (Mnemiopsis), dedicated duplicated gene pro- cephalopod (Loligo) embryo, demosponge (Amphimedon), nematode (Caenorhabditis) embryo, placozoan (Trichoplax), and moters (19). echinoderm (Dendraster) larva.

218

12 OCTOBER 2012

VOL 338

SCIENCE

www.sciencemag.org

Downloaded from www.sciencemag.org on January 15, 2013

SPECIALSECTION
2. S. Sick, S. Reinker, J. Timmer, chemically and mechanically acT. Schlake, Science 314, 1447 tive soft materials. However, just (2006). Mollusks Chordates Ecdysozoans as nonliving materials do not 3. I. Salazar-Ciudad, J. Jernvall, Nature equally engage every physical 464, 583 (2010). 4. A. C. Oates, L. G. Morelli, S. Ares, effect, not every DPM appears Development 139, 625 (2012). in each animal lineage, because Annelids Flatworms Echinoderms 5. S. Conway Morris, Philos. Trans. the relevant genes are not uniR. Soc. London Ser. B 361, 1069 versally present throughout the (2006). 6. J. D. Amack, M. L. Manning, Science metazoan phyla. The fundamenCnidarians Ctenophores 338, 212 (2012). tal DPM is adhesion (mediated 7. L. A. Davidson, Curr. Top. Dev. Biol. mainly by cadherins), which 95, 215 (2011). would have generated proto8. M. J. Harrington, E. Hong, R. Brewster, Placozoans Sponges metazoan clusters (Fig. 2). Such Mol. Reprod. Dev. 76, 954 (2009). 9. M. Laurent, N. Kellershohn, clusters, with appropriate DPMTrends Biochem. Sci. 24, 418 enabling genes, could have ex(1999). hibited more-complex body plans Ancestral protometazoan cell clusters 10. H. Reinke, D. Gatfield, Trends (Fig. 1, curved red arrow), but, as Biochem. Sci. 31, 189 (2006). 11. J. J. Tyson, B. Novak, Curr. Biol. 21, noted above, would have lost out Increasing morphological complexity R185 (2011). to lineages arising by cleavage 12. S. H. Strogatz, Sync: The Emerging (Fig. 1, straight green arrows). Science of Spontaneous Order (Theia, The formation of non-intermixed Fig. 2. The increasing complexity of animal body plans during evolution depended New York, ed. 1, 2003). on the mobilization of new DPMs. The lines of descent of the various morophotypes 13. Y. Masamizu et al., Proc. Natl. Acad. layers, as in placozoans (Fig. 1), are uncertain because of the possibility of gene loss and lateral transfer. Sci. U.S.A. 103, 1313 (2006). depended on differential in14. A. M. Turing, Philos. Trans. R. Soc. terfacial tension (meditated by London Ser. B 237, 37 (1952). cadherins in conjuction with cytoskeletal me- vertebrates, arthropods, nematodes, mollusks, and 15. H. Meinhardt, Curr. Top. Dev. Biol. 81, 1 (2008). chanics) and apicobasal cell polarity (mediated echinoderms (Fig. 1). 16. A. Kicheva, M. Cohen, J. Briscoe, Science 338, 210 (2012). The idea that physics acted on early multiby the canonical Wnt pathway). Lateral inhi17. S. Kondo, T. Miura, Science 329, 1616 (2010). bition [mediated by the Notch pathway, absent cellular forms to define in broad strokes the pat18. D. E. Clyde et al., Nature 426, 849 (2003). in Trichoplax (27)] and a viscous, generalized terns of development resolves several seemingly 19. M. Akam, Nature 341, 282 (1989). (i.e., not epithelial or mesenchymal) extracellu- paradoxical aspects of the evolution of the animal 20. S. A. Newman, G. Forgacs, G. B. Mller, Int. J. Dev. Biol. lar matrix allowed the coexistence and rearrange- phyla. These include the rapid emergence (in two 50, 289 (2006). 21. A. S. Wilkins, The Evolution of Developmental Pathways ment of contiguous intertransforming cells, as episodes of approximately 20 million years each) (Sinauer Associates, Sunderland, MA, 2002). in sponges (Fig. 1). Planar polarity (mediated of nearly all of the metazoan body plans during 22. S. A. Newman, R. Bhat, Int. J. Dev. Biol. 53, 693 by the noncanical Wnt pathway) and a basal the late Ediacaranearly Cambrian periods (5, 30); (2009). lamina-type extracellular matrix [both absent in the use of the same genetic tool kit to mediate 23. N. King et al., Nature 451, 783 (2008). genetically characterized sponges and placozoans similar morphogenetic processes in all animal 24. K. Shalchian-Tabrizi et al., PLoS ONE 3, e2098 (2008). (2729)] enabled the formation of elongated phyla, however disparate (21); the recurrent ap25. R. K. Grosberg, R. Strathmann, Annu. Rev. Ecol. Evol. Syst. bodies and epithelial appendages and ridges, as pearance of a limited set of morphological motifs 38, 621 (2007). in ctenophores (Fig. 1) and cndarians. An inter- in all animal body plans and organ forms (20, 22); 26. S. A. Newman, J. Exp. Zoolog. B Mol. Dev. Evol. 316B, stitial extracellular matrix allowed for epithelial- and the relative insensitivity of phylum-associated 467 (2011). mesenchymal transformation and intereactions, morphological signatures to variations at stages 27. M. Srivastava et al., Nature 454, 955 (2008). and triploblasty (i.e., three-layered structures). of development before the multicellular one, when 28. M. Srivastava et al., Nature 466, 720 (2010). 29. M. Adamska et al., PLoS ONE 2, e1031 (2007). Extracellular matrices with distinctive physical DPMs come into play (26). 30. B. Shen, L. Dong, S. Xiao, M. Kowalewski, Science 319, properties (e.g., chitin versus collagen) and het81 (2008). References erochrony in the developmental implementation 1. G. Forgacs, S. A. Newman, Biological Physics of the of various shared DPMs led to disparate body Developing Embryo (Cambridge Univ. Press, Cambridge, 10.1126/science.1222003 plans among the triploblasts (Fig. 2), including 2005).

Metazoans

Eumetazoans

Triploblasts

www.sciencemag.org

SCIENCE

VOL 338

12 OCTOBER 2012

219

Downloaded from www.sciencemag.org on January 15, 2013