- Email: [email protected]
Left–Right Asymmetry: Actin–Myosin through the Looking Glass
Current Biology Vol 16 No 13 R502
why such preferences should be long-lasting, if indeed they last longer than the seven days demonstrated by Darmaillacq et al. [1]. In both sexual and filial imprinting — animal imprints on features of mother or siblings [7] — the benefits to both the timing and duration of the imprinting are reasonably clear: life-long retention of the memories of the features of siblings will be useful for all mate choices so as to avoid inbreeding. Likewise, learning the adult features of members of your species so as to avoid mating with the wrong species will not become redundant, even as experience of mate choice (and with the outcomes of that choice) increases. Food imprinting, on the other hand, would seem less valuable in the long term. For any long-lived animal, in particular one living in even somewhat changeable environments, a durable food preference may even be costly. In humans, for example, food preferences developed during childhood may contribute to poor eating patterns in adulthood [8]. Understanding the role of learning mechanisms such as imprinting, and the importance of sensory and
social context on food preferences, may shed light on what appear to be inappropriate food choices and consumption patterns, for example, over-consumption of foods high in sugar and fat [9,10]. Finally, determining the existence of, and the context in which food imprinting occurs, across species will aid our understanding of the generality of learning mechanisms. There continues to be debate as to whether natural selection has shaped the occurrence or kind of learning abilities animals possess [11]. The discovery, for example, that not all animals imprint on food would contribute to the question of whether or not there are adaptive specialisations in cognition (for example [12])? References 1. Darmaillacq, A.S., Chichery, M.P., and Dickel, L. (2006). Food imprinting, new evidence from cuttlefish Sepia officinalis. Biol. Lett. FirstCite, 1–3. 2. Wansink, B. (2002). Changing eating habits on the home front: Lost lessons from World War II research. J. Pub. Pol. Market. 21, 90–99. 3. Punzo, F. (2002). Early experience and prey preference in the lynx spider, Oxyopes salticus Hentz (Araneae: Oxyopidae). J.N.Y. Ent. Soc. 110, 255–259. 4. Darmaillacq, A.S., Chichery, R., Shashar, N., and Dickel, L. (2006). Early
Left–Right Asymmetry: Actin– Myosin through the Looking Glass Despite being bilaterally symmetric, most Metazoa exhibit clear, genetically determined left–right differences. In several animals, microtubule-based structures are thought to be the source of chiral information used to establish handedness. Now, two new studies in Drosophila identify a role for unconventional myosin motors in this process. Buzz Baum ‘If events show a certain dissymmetry, the same dissymmetry should be revealed in their causes.’ Pierre Curie, 1894.
Although bilateral animals appear left–right (L–R) symmetric from the outside, their internal organs often exhibit stereotypical L–R differences in their position and morphology [1,2]. Our hearts, for
example, are usually on our left-hand side. Although it is still not clear how this difference between the left and right sides of embryos is specified, the process is known to be under genetic control [3]. Surprisingly, when genes required for L–R patterning were first cloned, several were found to code for components of tubulin-based cilia: including two microtubulebased motors [4,5], prompting the search for a causal link between
5.
6.
7. 8.
9.
10.
11.
12.
familiarization overrides innate prey preference in newly hatched Sepia officinalis cuttlefish. Anim. Behav. 71, 511–514. Darmaillacq, A.S., Chichery, R., Poirier, R., and Dickel, L. (2004). Effect of early feeding experience on subsequent prey preference by cuttlefish, Sepia officinalis. Devel. Psychobiol. 45, 239–244. ten Cate, C., and Vos, D.R. (1999). Sexual imprinting and evolutionary processes in birds: A reassessment. Adv. Stud. Behav. 28, 1–31. Lorenz, K. (1937). The companion in the bird’s world. Auk 54, 245–273. Cashdan, E. (1994). A sensitive period for learning about food. Hum. Nat. 5, 279–291. Cooke, L., Wardle, J., and Gibson, E.L. (2003). Relationship between parental report of food neophobia and everyday food consumption in 2-6-year-old children. Appetite 41, 205–206. Drewnowski, A. (1997). Taste preference and food intake. Annu. Rev. Nutrition 17, 237–253. Healy, S.D., de Kort, S.R., and Clayton, N.S. (2005). The hippocampus, spatial memory and food hoarding: a puzzle revisited. Trends Ecol. Evol. 20, 17–22. Ratcliffe, J.M., Fenton, M.B., and Galef, B.G. (2003). An exception to the rule: common vampire bats do not learn taste aversions. Anim. Behav. 65, 385–389.
Institute of Evolutionary Biology, University of Edinburgh, Edinburgh EH9 3JT, UK. E-mail: [email protected]
DOI: 10.1016/j.cub.2006.06.013
cilia and L–R patterning. The results were spectacular: it was discovered that in the early mouse embryo, in a structure called ‘the node’, ordered rows of tilted cilia rotate in a clockwise direction to power a leftward flow of extracellular fluid [3]. As artificially reversing this flow is sufficient to reverse L–R symmetry [6], the cilia-based movement is likely to play a causal role in L–R symmetry breaking — perhaps through the establishment of a gradient of an extracellular signalling molecule or through mechanosensation [3]. Although the case in mouse is compelling, cilia do not appear to be at the right place and time to be involved in the establishment of handedness in a variety of other systems [7,8]. Hence the significance of the recent discovery of a role for myosin I motors in the regulation of handedness in the
Dispatch R503
fruit fly [9,10]. Flies have an exquisitely symmetric cuticle, but some internal structures are L–R asymmetric, including a twisted gut and genitalia. Therefore, to identify genes involved in the establishment of handedness, Speder et al. [9] and Hozumi et al. [10] screened fly embryos for mutations that cause defects in the looping of the gut and in genital disc rotation. Remarkably, both screens identified an actin-based motor, Myo31DF [9,10]. In the absence of Myo31DF, structures that normally loop one way now loop the opposite way, generating ‘looking-glass’ flies that are both viable and fertile (Figure 1). Because symmetry is not randomized in the mutants, Myo31DF is likely to function in the context of a more complex system to break L–R symmetry. This idea is validated by the demonstration that overexpression of Myo61F, a related myosin I family member, mimics loss of Myo31DF, reversing the looping of the midgut, hindgut and testes [10]. Interestingly, the foregut expresses Myo61F (K. Matsuno, personal communication), but not Myo31DF and is unaffected by loss of Myo31DF [10,11]. In addition, in this tissue handedness is reversed by the uniform expression of Myo31DF, but not Myo61F. These results show that Myo31DF and Myo61F play antagonistic roles in the regulation of L-R symmetrybreaking. As the foregut and hindgut follow a similar morphogenetic program, in which a bend along the dorso–ventral (D–V) axis is rotated by 90 degrees to generate a sinistral loop [12], it also presents a conundrum. Why does a different myosin I family member dominate in different tissues, and how can Myo31DF induce a sinistral twist in the hindgut and a dextral twist when expressed in the foregut? More work needs to be done to reveal the pathway from myosin I function to asymmetric morphogenesis. However, these results suggest that Myo31DF and Myo61F are more likely to interact with existing axial cues to initiate L–R symmetry breaking than to bias the process of loop formation itself.
A
B
C
D
E
fg
mg hg
R
L R
L R
L L
R
R Current Biology
Figure 1. Left-right asymmetry in Drosophila. Images show dorsal and ventral views of Drosophila embryos. In Myo31DF mutants (B,E), midgut (mg) and hindgut (hg) looping is reversed compared to wild-type (A,D). Overexpression of Myo31DF has no effect in most tissues but reverses the direction of foregut (fg) looping (C). With permission from [10].
The studies by Speder et al. [9] and Hozumi et al. [10] also show that the rotation of a single tissue, such as the foregut, can be reversed in an otherwise normal animal. This proves that in Drosophila handedness is a tissue-specific trait, instead of being globally defined, like the anterior–posterior (A–P) and D–V axes. Because of this, genetic tricks can be used to perturb Myo31DF expression during metamorphosis to turn a normal fly larva into its mirror image adult. Speder et al. [9] were able to use similar tools to show that cortically localized Myo31DF acts during a three hour period of metamorphosis in the A8 segment of the genital disc to control the dextral looping of the testes. As the A8 segment contributes little to the adult, the structure acts as an ‘organizer’ to direct the rotation of the entire genital disc epithelium [9]. Therefore, although the fly lacks an overall L–R axis, handedness information can be communicated between adjacent tissues to coordinate morphogenesis. How might myosin I motors generate L–R handedness? To begin answering this question, it is important to recognize that the establishment of the two major orthogonal axes of an embryo predetermines which is the left and which is the right side [13]. As a consequence, objective chiral information is required as a point of reference to accurately specify left and right after the establishment of the two primary orthogonal axes
[13]. Because few sources of objective chiral information are available to an embryo (plants frequently use the rotation of earth as a guide to spiral growth), we can expect this information to be derived from a molecular template that is stably oriented with respect to the A–P and D–V axes. Semirigid actin and microtubule based filaments seem to be good candidates for the source of L–R asymmetry [1,14]. Once L–R symmetry has been broken at the molecular scale, the challenge is to amplify this polar signal and translate it into asymmetric tissue organization. The decision to implement L–R symmetry-breaking, however, can be carried out autonomously and delayed indefinitely in any tissue that is able to read local A–P and D–V axial information. In identifying myosin I as a regulator of chirality, the work of Speder et al. [9] and Hozumi et al. [10] suggests that in flies ATP-dependent movement of myosin I motors along the right-handed helical twist of individual actin filaments is the most likely source of chiral information [9,10,15]. To distinguish left from right, actin filaments must be organized in parallel bundles, like those seen within the microvilli in the developing fly gut. In support of this idea, in other systems, myosin I motors play an important role in microvilli morphogenesis and can be seen in electron micrographs forming a helical staircase of cross-bridges linking actin filament
Current Biology Vol 16 No 13 R504
bundles to the membrane of gut microvilli [16], where they are thought to drive membrane towards the tips of protrusions. Although it is not yet clear whether myosin I homologues play a similar role in the fly, Myo31DF and Myo61F are found localized to the brush borders of fly hindgut epithelial cells soon after the gut has taken on its characteristic sinistral twist [11]. In addition, over-expression of the ERM-protein Moesin, another key regulator of microvilli structure, randomizes the direction of Myo31DF and Myo61F dependent L–R morphogenesis [10], suggesting a link between L–R symmetry-breaking and microvilli. As Myo31DF and Myo61F are both expected to move towards the barbed ends of actin filaments, the functional antagonism between these motors is likely to be mediated by differences in their cargo. The conserved IQ domains of myosin I may also play a role since they are essential for symmetry breaking [9], and target a mouse myosin I to brush borders [17]. In a search for relevant cargo, Speder et al. [9] identified beta-catenin bound to the tail domain of Myo31DF. Intriguingly, beta-catenin also binds Inversin, the only protein capable of reversing L–R determination in the mouse [18–20], where it may be linked to cadherin-mediated adhesion or Wnt signalling. These data point to a possible link between these processes in the mouse and fly. Clearly, more has to be done before we understand the functions of Myo31DF and Myo61F in L–R symmetry-breaking. But, given the excitement generated by these findings, we will soon learn whether the functions of myosin I motors in other bilateral animals mirror those of Myo31DF and Myo61F in the fly.
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Randomization of left-right asymmetry due to loss of nodal cilia generating leftward flow of extraembryonic fluid in mice lacking KIF3B motor protein. Cell 95, 829–837. Okada, Y., Nonaka, S., Tanaka, Y., Saijoh, Y., Hamada, H., and Hirokawa, N. (1999). Abnormal nodal flow precedes situs inversus in iv and inv mice. Mol. Cell 4, 459–468. Nonaka, S., Shiratori, H., Saijoh, Y., and Hamada, H. (2002). Determination of left-right patterning of the mouse embryo by artificial nodal flow. Nature 418, 96–99. Levin, M. (2005). Left-right asymmetry in embryonic development: a comprehensive review. Mech. Dev. 122, 3–25. Shibazaki, Y., Shimizu, M., and Kuroda, R. (2004). Body handedness is directed by genetically determined cytoskeletal dynamics in the early embryo. Curr. Biol. 14, 1462–1467. Speder, P., Adam, G., and Noselli, S. (2006). Type ID unconventional myosin controls left-right asymmetry in Drosophila. Nature 440, 803–807. Hozumi, S., Maeda, R., Taniguchi, K., Kanai, M., Shirakabe, S., Sasamura, T., Speder, P., Noselli, S., Aigaki, T., Murakami, R., et al. (2006). An unconventional myosin in Drosophila reverses the default handedness in visceral organs. Nature 440, 798–802. Morgan, N.S., Heintzelman, M.B., and Mooseker, M.S. (1995). Characterization of myosin-IA and myosin-IB, two unconventional myosins associated with the Drosophila brush border cytoskeleton. Dev. Biol. 172, 51–71. Hayashi, T., and Murakami, R. (2001). Left-right asymmetry in Drosophila melanogaster gut development. Dev. Growth Differ. 43, 239–246. Brown, N.A., and Wolpert, L. (1990). The development of handedness in left/right asymmetry. Development 109, 1–9. Hayashi, M., Aono, H., Ishihara, J., Oshima, S., Yamamoto, H., Nakazato, Y.,
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Ludwig Institute for Cancer Research, 91 Riding House Street, London W1W 7BS, UK. E-mail: [email protected]
DOI: 10.1016/j.cub.2006.06.011
T-Cell Memory: The Importance of Chemokine-Mediated Cell Attraction A recent study demonstrates the involvement of certain chemokines in immune response initiation and CD8+ T-cell memory formation. These seminal findings broaden our understanding of the role of chemokines in adaptive immune processes. Bernhard Moser
References 1. Wood, W.B. (1998). Handed asymmetry in nematodes. Semin. Cell Dev. Biol. 9, 53–60. 2. Wandelt, J., and Nagy, L.M. (2004). Left-right asymmetry: more than one way to coil a shell. Curr. Biol. 14, R654–R656. 3. Hirokawa, N., Tanaka, Y., Okada, Y., and Takeda, S. (2006). Nodal flow and the generation of left-right asymmetry. Cell 125, 33–45. 4. Nonaka, S., Tanaka, Y., Okada, Y., Takeda, S., Harada, A., Kanai, Y., Kido, M., and Hirokawa, N. (1998).
15.
and Kobayashi, S. (2005). Left-right asymmetry in the alimentary canal of the Drosophila embryo. Dev. Growth Differ. 47, 457–460. Ali, M.Y., Uemura, S., Adachi, K., Itoh, H., Kinosita, K., Jr., and Ishiwata, S. (2002). Myosin V is a left-handed spiral motor on the right-handed actin helix. Nat. Struct. Biol. 9, 464–467. Tyska, M.J., Mackey, A.T., Huang, J.D., Copeland, N.G., Jenkins, N.A., and Mooseker, M.S. (2005). Myosin-1a is critical for normal brush border structure and composition. Mol. Biol. Cell 16, 2443–2457. Cyr, J.L., Dumont, R.A., and Gillespie, P.G. (2002). Myosin-1c interacts with hair-cell receptors through its calmodulin-binding IQ domains. J. Neurosci. 22, 2487–2495. Simons, M., Gloy, J., Ganner, A., Bullerkotte, A., Bashkurov, M., Kronig, C., Schermer, B., Benzing, T., Cabello, O.A., Jenny, A., et al. (2005). Inversin, the gene product mutated in nephronophthisis type II, functions as a molecular switch between Wnt signaling pathways. Nat. Genet. 37, 537–543. Nurnberger, J., Bacallao, R.L., and Phillips, C.L. (2002). Inversin forms a complex with catenins and N-cadherin in polarized epithelial cells. Mol. Biol. Cell 13, 3096–3106. Morgan, D., Goodship, J., Essner, J.J., Vogan, K.J., Turnpenny, L., Yost, H.J., Tabin, C.J., and Strachan, T. (2002). The left-right determinant inversin has highly conserved ankyrin repeat and IQ domains and interacts with calmodulin. Hum. Genet. 110, 377–384.
Chemokines represent a class of pro-inflammatory cytokines that have the ability to attract and activate leukocytes. Our current knowledge about chemokines and adhesion molecules underscores the strict relationship between leukocyte localization and leukocyte function [1,2]. In the case
of T- and B-cell responses, three key events are regulated by chemokines, namely pathogen contact and processing in the tissue, immune response initiation in the draining lymph node, and pathogen neutralization by newly generated, pathogen-specific effector cells. Recent work by Ron Germain and colleagues [3] now demonstrates that chemokines
why such preferences should be long-lasting, if indeed they last longer than the seven days demonstrated by Darmaillacq et al. [1]. In both sexual and filial imprinting — animal imprints on features of mother or siblings [7] — the benefits to both the timing and duration of the imprinting are reasonably clear: life-long retention of the memories of the features of siblings will be useful for all mate choices so as to avoid inbreeding. Likewise, learning the adult features of members of your species so as to avoid mating with the wrong species will not become redundant, even as experience of mate choice (and with the outcomes of that choice) increases. Food imprinting, on the other hand, would seem less valuable in the long term. For any long-lived animal, in particular one living in even somewhat changeable environments, a durable food preference may even be costly. In humans, for example, food preferences developed during childhood may contribute to poor eating patterns in adulthood [8]. Understanding the role of learning mechanisms such as imprinting, and the importance of sensory and
social context on food preferences, may shed light on what appear to be inappropriate food choices and consumption patterns, for example, over-consumption of foods high in sugar and fat [9,10]. Finally, determining the existence of, and the context in which food imprinting occurs, across species will aid our understanding of the generality of learning mechanisms. There continues to be debate as to whether natural selection has shaped the occurrence or kind of learning abilities animals possess [11]. The discovery, for example, that not all animals imprint on food would contribute to the question of whether or not there are adaptive specialisations in cognition (for example [12])? References 1. Darmaillacq, A.S., Chichery, M.P., and Dickel, L. (2006). Food imprinting, new evidence from cuttlefish Sepia officinalis. Biol. Lett. FirstCite, 1–3. 2. Wansink, B. (2002). Changing eating habits on the home front: Lost lessons from World War II research. J. Pub. Pol. Market. 21, 90–99. 3. Punzo, F. (2002). Early experience and prey preference in the lynx spider, Oxyopes salticus Hentz (Araneae: Oxyopidae). J.N.Y. Ent. Soc. 110, 255–259. 4. Darmaillacq, A.S., Chichery, R., Shashar, N., and Dickel, L. (2006). Early
Left–Right Asymmetry: Actin– Myosin through the Looking Glass Despite being bilaterally symmetric, most Metazoa exhibit clear, genetically determined left–right differences. In several animals, microtubule-based structures are thought to be the source of chiral information used to establish handedness. Now, two new studies in Drosophila identify a role for unconventional myosin motors in this process. Buzz Baum ‘If events show a certain dissymmetry, the same dissymmetry should be revealed in their causes.’ Pierre Curie, 1894.
Although bilateral animals appear left–right (L–R) symmetric from the outside, their internal organs often exhibit stereotypical L–R differences in their position and morphology [1,2]. Our hearts, for
example, are usually on our left-hand side. Although it is still not clear how this difference between the left and right sides of embryos is specified, the process is known to be under genetic control [3]. Surprisingly, when genes required for L–R patterning were first cloned, several were found to code for components of tubulin-based cilia: including two microtubulebased motors [4,5], prompting the search for a causal link between
5.
6.
7. 8.
9.
10.
11.
12.
familiarization overrides innate prey preference in newly hatched Sepia officinalis cuttlefish. Anim. Behav. 71, 511–514. Darmaillacq, A.S., Chichery, R., Poirier, R., and Dickel, L. (2004). Effect of early feeding experience on subsequent prey preference by cuttlefish, Sepia officinalis. Devel. Psychobiol. 45, 239–244. ten Cate, C., and Vos, D.R. (1999). Sexual imprinting and evolutionary processes in birds: A reassessment. Adv. Stud. Behav. 28, 1–31. Lorenz, K. (1937). The companion in the bird’s world. Auk 54, 245–273. Cashdan, E. (1994). A sensitive period for learning about food. Hum. Nat. 5, 279–291. Cooke, L., Wardle, J., and Gibson, E.L. (2003). Relationship between parental report of food neophobia and everyday food consumption in 2-6-year-old children. Appetite 41, 205–206. Drewnowski, A. (1997). Taste preference and food intake. Annu. Rev. Nutrition 17, 237–253. Healy, S.D., de Kort, S.R., and Clayton, N.S. (2005). The hippocampus, spatial memory and food hoarding: a puzzle revisited. Trends Ecol. Evol. 20, 17–22. Ratcliffe, J.M., Fenton, M.B., and Galef, B.G. (2003). An exception to the rule: common vampire bats do not learn taste aversions. Anim. Behav. 65, 385–389.
Institute of Evolutionary Biology, University of Edinburgh, Edinburgh EH9 3JT, UK. E-mail: [email protected]
DOI: 10.1016/j.cub.2006.06.013
cilia and L–R patterning. The results were spectacular: it was discovered that in the early mouse embryo, in a structure called ‘the node’, ordered rows of tilted cilia rotate in a clockwise direction to power a leftward flow of extracellular fluid [3]. As artificially reversing this flow is sufficient to reverse L–R symmetry [6], the cilia-based movement is likely to play a causal role in L–R symmetry breaking — perhaps through the establishment of a gradient of an extracellular signalling molecule or through mechanosensation [3]. Although the case in mouse is compelling, cilia do not appear to be at the right place and time to be involved in the establishment of handedness in a variety of other systems [7,8]. Hence the significance of the recent discovery of a role for myosin I motors in the regulation of handedness in the
Dispatch R503
fruit fly [9,10]. Flies have an exquisitely symmetric cuticle, but some internal structures are L–R asymmetric, including a twisted gut and genitalia. Therefore, to identify genes involved in the establishment of handedness, Speder et al. [9] and Hozumi et al. [10] screened fly embryos for mutations that cause defects in the looping of the gut and in genital disc rotation. Remarkably, both screens identified an actin-based motor, Myo31DF [9,10]. In the absence of Myo31DF, structures that normally loop one way now loop the opposite way, generating ‘looking-glass’ flies that are both viable and fertile (Figure 1). Because symmetry is not randomized in the mutants, Myo31DF is likely to function in the context of a more complex system to break L–R symmetry. This idea is validated by the demonstration that overexpression of Myo61F, a related myosin I family member, mimics loss of Myo31DF, reversing the looping of the midgut, hindgut and testes [10]. Interestingly, the foregut expresses Myo61F (K. Matsuno, personal communication), but not Myo31DF and is unaffected by loss of Myo31DF [10,11]. In addition, in this tissue handedness is reversed by the uniform expression of Myo31DF, but not Myo61F. These results show that Myo31DF and Myo61F play antagonistic roles in the regulation of L-R symmetrybreaking. As the foregut and hindgut follow a similar morphogenetic program, in which a bend along the dorso–ventral (D–V) axis is rotated by 90 degrees to generate a sinistral loop [12], it also presents a conundrum. Why does a different myosin I family member dominate in different tissues, and how can Myo31DF induce a sinistral twist in the hindgut and a dextral twist when expressed in the foregut? More work needs to be done to reveal the pathway from myosin I function to asymmetric morphogenesis. However, these results suggest that Myo31DF and Myo61F are more likely to interact with existing axial cues to initiate L–R symmetry breaking than to bias the process of loop formation itself.
A
B
C
D
E
fg
mg hg
R
L R
L R
L L
R
R Current Biology
Figure 1. Left-right asymmetry in Drosophila. Images show dorsal and ventral views of Drosophila embryos. In Myo31DF mutants (B,E), midgut (mg) and hindgut (hg) looping is reversed compared to wild-type (A,D). Overexpression of Myo31DF has no effect in most tissues but reverses the direction of foregut (fg) looping (C). With permission from [10].
The studies by Speder et al. [9] and Hozumi et al. [10] also show that the rotation of a single tissue, such as the foregut, can be reversed in an otherwise normal animal. This proves that in Drosophila handedness is a tissue-specific trait, instead of being globally defined, like the anterior–posterior (A–P) and D–V axes. Because of this, genetic tricks can be used to perturb Myo31DF expression during metamorphosis to turn a normal fly larva into its mirror image adult. Speder et al. [9] were able to use similar tools to show that cortically localized Myo31DF acts during a three hour period of metamorphosis in the A8 segment of the genital disc to control the dextral looping of the testes. As the A8 segment contributes little to the adult, the structure acts as an ‘organizer’ to direct the rotation of the entire genital disc epithelium [9]. Therefore, although the fly lacks an overall L–R axis, handedness information can be communicated between adjacent tissues to coordinate morphogenesis. How might myosin I motors generate L–R handedness? To begin answering this question, it is important to recognize that the establishment of the two major orthogonal axes of an embryo predetermines which is the left and which is the right side [13]. As a consequence, objective chiral information is required as a point of reference to accurately specify left and right after the establishment of the two primary orthogonal axes
[13]. Because few sources of objective chiral information are available to an embryo (plants frequently use the rotation of earth as a guide to spiral growth), we can expect this information to be derived from a molecular template that is stably oriented with respect to the A–P and D–V axes. Semirigid actin and microtubule based filaments seem to be good candidates for the source of L–R asymmetry [1,14]. Once L–R symmetry has been broken at the molecular scale, the challenge is to amplify this polar signal and translate it into asymmetric tissue organization. The decision to implement L–R symmetry-breaking, however, can be carried out autonomously and delayed indefinitely in any tissue that is able to read local A–P and D–V axial information. In identifying myosin I as a regulator of chirality, the work of Speder et al. [9] and Hozumi et al. [10] suggests that in flies ATP-dependent movement of myosin I motors along the right-handed helical twist of individual actin filaments is the most likely source of chiral information [9,10,15]. To distinguish left from right, actin filaments must be organized in parallel bundles, like those seen within the microvilli in the developing fly gut. In support of this idea, in other systems, myosin I motors play an important role in microvilli morphogenesis and can be seen in electron micrographs forming a helical staircase of cross-bridges linking actin filament
Current Biology Vol 16 No 13 R504
bundles to the membrane of gut microvilli [16], where they are thought to drive membrane towards the tips of protrusions. Although it is not yet clear whether myosin I homologues play a similar role in the fly, Myo31DF and Myo61F are found localized to the brush borders of fly hindgut epithelial cells soon after the gut has taken on its characteristic sinistral twist [11]. In addition, over-expression of the ERM-protein Moesin, another key regulator of microvilli structure, randomizes the direction of Myo31DF and Myo61F dependent L–R morphogenesis [10], suggesting a link between L–R symmetry-breaking and microvilli. As Myo31DF and Myo61F are both expected to move towards the barbed ends of actin filaments, the functional antagonism between these motors is likely to be mediated by differences in their cargo. The conserved IQ domains of myosin I may also play a role since they are essential for symmetry breaking [9], and target a mouse myosin I to brush borders [17]. In a search for relevant cargo, Speder et al. [9] identified beta-catenin bound to the tail domain of Myo31DF. Intriguingly, beta-catenin also binds Inversin, the only protein capable of reversing L–R determination in the mouse [18–20], where it may be linked to cadherin-mediated adhesion or Wnt signalling. These data point to a possible link between these processes in the mouse and fly. Clearly, more has to be done before we understand the functions of Myo31DF and Myo61F in L–R symmetry-breaking. But, given the excitement generated by these findings, we will soon learn whether the functions of myosin I motors in other bilateral animals mirror those of Myo31DF and Myo61F in the fly.
5.
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Ludwig Institute for Cancer Research, 91 Riding House Street, London W1W 7BS, UK. E-mail: [email protected]
DOI: 10.1016/j.cub.2006.06.011
T-Cell Memory: The Importance of Chemokine-Mediated Cell Attraction A recent study demonstrates the involvement of certain chemokines in immune response initiation and CD8+ T-cell memory formation. These seminal findings broaden our understanding of the role of chemokines in adaptive immune processes. Bernhard Moser
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Chemokines represent a class of pro-inflammatory cytokines that have the ability to attract and activate leukocytes. Our current knowledge about chemokines and adhesion molecules underscores the strict relationship between leukocyte localization and leukocyte function [1,2]. In the case
of T- and B-cell responses, three key events are regulated by chemokines, namely pathogen contact and processing in the tissue, immune response initiation in the draining lymph node, and pathogen neutralization by newly generated, pathogen-specific effector cells. Recent work by Ron Germain and colleagues [3] now demonstrates that chemokines