(Entry #4 for the week of science)
While I work with mammalian cells (mouse, human, etc.), the basic model organism of choice for studying chemotaxis and cell migration is Dictyostelium discoideum, or Dicty for short. This is a soil-living social amoeba grows as separate, independent cells that interact to form multicellular structures when challenged by adverse conditions such as starvation. Up to 100,000 cells signal each other by releasing the chemoattractant cAMP and aggregate together by chemotaxis to form a mound that is surrounded by an extracellular matrix. This mechanism for generating a multicellular organism differs radically from the early steps of metazoan embryogenesis. However, subsequent processes depend on cell-cell communication in both Dictyostelium and metazoans. Many of the underlying molecular and cellular processes appear to have arisen in primitive precursor cells and to have remained fundamentally unchanged throughout evolution. Basic processes of development such as differential cell sorting, pattern formation, stimulus-induced gene expression, and cell-type regulation are common to Dictyostelium and metazoans.
One of the incredible strengths of this model system is the capacity to track the dynamic behaviors of individual cells, yet still can function as a collective of cells. This makes Dicty the best of both worlds – an easily studied single cell organism for one half of its life cycle, and a multicellular creature during the other half, such that it can inform us on the fundamental principles of cell behavior.
Another strength is the accessibility of phenotypes and biochemistry, since the simplicity of the life cycle facilitates mutant selection. The growth and developmental stages are completely independent, and switching between the two states is achieved by removing nutrients. Many mutations can be screened by clonally plating cells on bacterial lawns. As the amoebae grow, they ingest the bacteria and form a plaque. The cells within the plaque starve and enter the developmental program. Aberrant phenotypes can be scored by visual inspection of the plaques. Since the early stages of development are readily reversible, mutants can be selected and then propagated by returning them to nutrients.
It also helps that the Dicty genome has been sequenced (Eichinger et al., 2005).
For an additional list, see these important breakthroughs achieved through generalizations for eukaryotic cells, that have been derived from studies of D. discoideum:
- Cytoskeletal proteins have overlapping functions. Detailed investigations of multiple gene deletions of myosins and actin binding proteins first demonstrated this now generally accepted concept.
- Cytoskeletal proteins and organelles dynamically relocalize within living cells during cytokinesis, motility, and phagocytosis. Actin, myosin, coronin, talin, cyclase-associated protein, and actin binding proteins move to related regions of the cell during each of these events. In addition, novel components of the cytoskeletal, including coronin, cortellexin, and scar having been discovered in Dictyostelium.
- Conventional myosin is required for cytokinesis. This was shown in D. discoideum over a decade ago and has recently been duplicated in yeast. Further studies of D. discoideum myosin heavy chain in vivo and as single molecules in vitro have provided many of the known characteristics of this molecular motor.
- Chemoattractants are sensed by G-protein coupled receptors. Over a decade ago, cloning and deletion of the cAMP receptors in D. discoideum showed that these receptors were essential for chemotaxis. It is now clear that a family of twenty G-protein linked “chemokine” receptors mediates chemotaxis in leukocytes.
- Gradient direction is sensed by selectively recruiting PH domains to the membrane. Neither surface receptors nor G-proteins are significantly clustered at the cell’s leading edge. In addition, the actin cytoskeleton is not required for PH domain recruitment. Many of these observations have recently been duplicated in mammalian leukocytes responding to chemokines.
- Chisholm RL, Gaudet P, Just EM, Pilcher KE, Fey P, Merchant SN, Kibbe WA. (2006) dictyBase, the model organism database for Dictyostelium discoideum. Nucleic Acids Res. 34 (Database issue): D423-7. Nucleic Acids Research
- Eichinger L, Pachebat JA, Glockner G, Rajandream MA, Sucgang R, Berriman M, Song J, Olsen R, Szafranski K, Xu Q, Tunggal B, Kummerfeld S, Madera M, Konfortov BA, Rivero F, Bankier AT, Lehmann R, Hamlin N, Davies R, Gaudet P, Fey P, Pilcher K, Chen G, Saunders D, Sodergren E, Davis P, Kerhornou A, Nie X, Hall N, Anjard C, Hemphill L, Bason N, Farbrother P, Desany B, Just E, Morio T, Rost R, Churcher C, Cooper J, Haydock S, van Driessche N, Cronin A, Goodhead I, Muzny D, Mourier T, Pain A, Lu M, Harper D, Lindsay R, Hauser H, James K, Quiles M, Madan Babu M, Saito T, Buchrieser C, Wardroper A, Felder M, Thangavelu M, Johnson D, Knights A, Loulseged H, Mungall K, Oliver K, Price C, Quail MA, Urushihara H, Hernandez J, Rabbinowitsch E, Steffen D, Sanders M, Ma J, Kohara Y, Sharp S, Simmonds M, Spiegler S, Tivey A, Sugano S, White B, Walker D, Woodward J, Winckler T, Tanaka Y, Shaulsky G, Schleicher M, Weinstock G, Rosenthal A, Cox EC, Chisholm RL, Gibbs R, Loomis WF, Platzer M, Kay RR, Williams J, Dear PH, Noegel AA, Barrell B, Kuspa A. (2005) The genome of the social amoeba Dictyostelium discoideum. Nature 435(7038): 43-57. Nature
- Baldauf SL, Doolittle WF. (1997) Origin and evolution of the slime molds (Mycetozoa). Proc Natl Acad Sci U S A 94(22):12007-12. PNAS