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3. Carpenter, A.T. (1975). Electron microscopy of duration are modified in spermatocytes at meiosis I. Proc. Natl. Acad. Sci. USA 107, meiosis in Drosophila melanogaster females. I. lacking axial elements. Mol. Biol. Cell 15, 781–785. Structure, arrangement, and temporal change 827–837. 12. Page, J., Viera, A., Parra, M.T., de la Fuente, R., of the synaptonemal complex in wild-type. 8. Eijpe, M., Offenberg, H., Jessberger, R., Suja, J.A., Prieto, I., Barbero, J.L., Rufas, J.S., Chromosoma 51, 157–182. Revenkova, E., and Heyting, C. (2003). Meiotic Berrios, S., and Fernandez-Donoso, R. (2006). 4. Nokkala, S., and Puro, J. (1976). Cytological cohesin REC8 marks the axial elements of rat Involvement of synaptonemal complex proteins evidence for a chromocenter in Drosophila synaptonemal complexes before cohesins in sex chromosome segregation during melanogaster oocytes. Hereditas 83, 265–268. SMC1beta and SMC3. J. Cell Biol. 160, marsupial male meiosis. PLoS Genet. 2, e136. 5. Takeo, S., Lake, C.M., Morais-de-Sa, E., 657–670. 13. Subramanian, V.V., and Bickel, S.E. (2009). Sunkel, C.E., and Hawley, R.S. (2011). 9. Tsubouchi, T., and Roeder, G.S. (2005). A Heterochromatin-mediated association of Synaptonemal complex-dependent synaptonemal complex protein promotes achiasmate homologs declines with age when centromeric clustering and the initiation of homology-independent centromere coupling. cohesion is compromised. Genetics 181, synapsis in Drosophila oocytes. Curr. Biol. 21, Science 308, 870–873. 1207–1218. 1845–1851. 10. Gladstone, M.N., Obeso, D., Chuong, H., and 6. Tanneti, N.S., Landy, K., Joyce, E.F., and Dawson, D.S. (2009). The synaptonemal McKim, K.S. (2011). A pathway for synapsis complex protein Zip1 promotes bi-orientation Department of Biology, New York University, initiation during zygotene in Drosophila of centromeres at meiosis I. PLoS Genet. 5, New York, NY 10003, USA. oocytes. Curr. Biol. 21, 1852–1857. e1000771. E-mail: [email protected] 7. Liebe, B., Alsheimer, M., Hoog, C., 11. Newnham, L., Jordan, P., Rockmill, B., Benavente, R., and Scherthan, H. (2004). Roeder, G.S., and Hoffmann, E. (2010). The Telomere attachment, meiotic chromosome synaptonemal complex protein, Zip1, promotes condensation, pairing, and bouquet stage the segregation of nonexchange chromosomes DOI: 10.1016/j.cub.2011.10.023

Organelle Dynamics: ER Embraces yeast or Drp1 in mammals. Members of the dynamin family are large GTPases Mitochondria for Fission that self-assemble into large helical oligomers that wrap around cellular membranes. Membrane tubulation The endoplasmic reticulum and mitochondria are engaged in an intimate and/or fission is then achieved by relationship: they establish extensive contacts, exchange lipids and calcium, mechanochemical forces released and coordinate their activities in cell life and death. Recent research has upon GTP hydrolysis [3]. The molecular revealed a new role for the endoplasmic reticulum in promoting mitochondrial machinery of mitochondrial fission has division. been studied in great detail, both in yeast and in mammals. In yeast, Benedikt Westermann potential to dissipate metabolic a mitochondrial outer membrane energy. It also allows intermixing and protein, Fis1, and a soluble adaptor Cellular organelles were long regarded exchange of mitochondrial content and protein, Mdv1, promote the assembly as separate entities that provide complementation of mitochondrial of cytosolic Dnm1 on the mitochondrial secluded compartments tailored for gene products, a process thought to surface, driving membrane scission specific cellular or metabolic reactions. counteract the decline of mitochondrial [4–6]. Similarly, mammalian Drp1 can This view has changed as it has been functions during aging. Mitochondrial be recruited to the mitochondrial recognized that organelles are highly fission, on the other hand, is required to surface by Fis1, albeit without the dynamic and interdependent. It is now generate organelles that are small participation of an Mdv1 homologue becoming clear that the intricate enough to be transported by molecular [7]. In addition, the outer membrane of architecture of a eukaryotic cell can be motors along the cytoskeleton. This is mammalian mitochondria contains established and maintained only particularly important in large, a Fis1-independent division protein, through coordinated and cooperative differentiated cells, such as neurons, Mff, which recruits Drp1 and is activity of its constituents. Now, in and during cell division. Moreover, essential for mitochondrial fission [8,9]. a recent article published in Science, mitochondrial fission is important for Although these and many other studies Friedman et al. [1] report that the the release of cytochrome c from the provided a wealth of data allowing endoplasmic reticulum (ER) plays an mitochondrial intermembrane space detailed insights into the mechanics of active role in defining the sites of into the cytosol to trigger apoptosis, mitochondrial division, two major mitochondrial division and thereby and it is thought to facilitate the questions remained unanswered. First, helps to shape the mitochondrial removal of damaged organelles by Dnm1 was observed to assemble on compartment. autophagy [2]. Given this multitude of many sites on yeast mitochondria, but Mitochondria are highly dynamic cellular functions, it is not surprising not every Dnm1 oligomer was found to organelles that frequently fuse and that defects in mitochondrial fusion promote a mitochondrial fission event divide. This dynamic behaviour and fission are associated with several [10]. Thus, it is not known how the determines mitochondrial morphology diseases, including age-associated mitochondrial division sites are and serves many important functions neurodegeneration or neonatal selected from the Dnm1 assembly [2]. The formation of large, death [2]. sites. And second, the diameter of interconnected mitochondrial The key protein mediating Dnm1 helices assembled on lipid tubes networks by the fusion of individual mitochondrial division is an in vitro (w100 nm) is much smaller than organelles facilitates the transmission evolutionarily conserved the diameter of a typical mitochondrial of the mitochondrial membrane dynamin-related protein called Dnm1 in tubule (w300 nm) [6]. So how can Dispatch R923 a narrow Dnm1 helix assemble on proteins are absent. Furthermore, it a rather thick mitochondrion? The was shown previously that disruption ER study by Friedman et al. [1] may hold of Drp1 function severely disturbs answers to both of these questions. morphology and distribution of the ER Dynamin-related A number of studies have revealed in mammalian cells [14]. Hence, the protein close contacts between the ER and membrane-shaping activities of the ER mitochondria by light and electron and mitochondria may be mutually microscopy [11,12]. Now, Friedman beneficial for both organelles. et al. [1] analyzed the What are the proteins that establish three-dimensional structure of the ER–mitochondria contacts at future contacts between mitochondria and fission sites? The answer to this Mitochondrion ER by electron tomography in yeast question is not known, but previously Current Biology cells. They observed that ER tubules described organelle-bridging proteins occasionally were wrapped around [15] are prime candidates. In yeast, Figure 1. ER-mediated constriction of mito- mitochondria, and in some instances a mitochondria–ER tethering complex chondrial division sites. almost completely circumscribed the was recently identified that is ER and mitochondria are frequently present mitochondrial surface. Intriguingly, the composed of subunits resident in both in close apposition. Membrane contact sites are thought to play important roles in the mitochondrial diameter was the ER and mitochondria. As this exchange of membrane lipids and calcium substantially reduced at the ER contact complex is localized at discrete foci at signalling [15]. Friedman et al. [1] identified domains, suggesting a potential role in sites of close apposition between ER a new type of ER–mitochondrial interface. mitochondrial constriction and/or and mitochondria, it was termed the ER tubules are wrapped around mitochon- division. By time-resolved live-cell ER–mitochondria encounter structure dria, sometimes almost completely circum- fluorescence microscopy the authors (ERMES) [16]. The fact that deletion of scribing the mitochondrial outer membrane. The diameter of mitochondrial tubules is observed that most of the any of its subunits results in severe significantly reduced at these sites, allowing mitochondrial division events indeed mitochondrial morphology defects [17] the assembly of relatively narrow spirals of occurred at ER contact sites, both in is compatible with a role for ERMES in dynamin-related protein oligomers that drive yeast and in mammalian cells. determining sites of mitochondrial mitochondrial division. Consistent with this observation, fission. Homologous genes encoding GFP-tagged Dnm1 or Drp1 was found ERMES subunits in mammals are as yet to assemble on mitochondria unknown. However, physical linkages mitochondrial fission? What are the preferentially at sites of of ER and mitochondria were found by physiological consequences of mitochondrial–ER contact. As shown in electron tomography [18] and disrupting or enhancing mitochondrial RNAi-treated mammalian cells, the biochemical approaches [19] in ER contacts? The observations by establishment of mitochondrial–ER mammalian cells. These contacts are Friedman et al. [1] offer an explanation contacts and mitochondrial thought to primarily function in calcium for how mitochondrial division sites are constriction was not dependent on the signalling. Interestingly, Friedman selected. This poses the next question mitochondrial fission proteins Mff or et al. [1] found that chelation of regarding how mitochondrial–ER Drp1 [1]. Taken together, these cytosolic calcium induces extensive interaction sites are selected. The observations assign to the ER an active mitochondrial division at ER contact answering of these and many more role in determining the sites of sites, pointing to a role of the ER in questions will keep cell biologists busy mitochondrial fission. In addition, it is mitochondrial division in response to for many more years. conceivable that the tight association calcium depletion. Furthermore, their References with the ER is important to constrict the results exclude at least one obvious 1. Friedman, J.R., Lackner, L.L., West, M., mitochondrial tubule sufficiently to fit candidate: mitofusin 2, which was DiBenedetto, J.R., Nunnari, J., and Voeltz, G.K. its diameter to that of the division shown previously to tether (2011). ER tubules mark sites of mitochondrial division. Science 334, 358–362. machinery consisting of spirals of mitochondria and ER [20], is not 2. Westermann, B. (2010). Mitochondrial fusion dynamin-related protein required for ER-mediated and fission in cell life and death. Nat. Rev. Mol. Cell Biol. 11, 872–884. oligomers (Figure 1). mitochondrial constriction [1]. 3. Praefcke, G.J., and McMahon, H.T. (2004). The ER and mitochondria are not The identification of the molecular dynamin superfamily: universal membrane engaged in a one-way relationship. The machinery mediating ER-assisted tubulation and fission molecules? Nat. Rev. Mol. Cell Biol. 5, 133–147. study by Friedman et al. [1] reports an mitochondrial constriction will no 4. Mozdy, A., McCaffery, J.M., and Shaw, J.M. intriguing observation that points to doubt be only the next step in a whole (2000). Dnm1p GTPase-mediated mitochondrial fusion is a multi-step process a role of mitochondria in shaping the series of exciting experiments and will requiring the novel integral membrane ER. Conserved ER membrane proteins, enable us to address many more component Fis1p. J. Cell Biol. 151, 367–379. termed reticulons, and DP1/Yop1 are important questions. What are the 5. Lackner, L.L., Horner, J.S., and Nunnari, J. (2009). Mechanistic analysis of a dynamin required to generate and maintain the forces driving mitochondrial effector. Science 325, 874–877. characteristic shape of ER tubules [13]. constriction? There are several 6. Mears, J.A., Lackner, L.L., Fang, S., Ingerman, E., Nunnari, J., and Hinshaw, J.E. While deletion of reticulons and Yop1 mutually non-exclusive possibilities: (2011). Conformational changes in Dnm1 disrupts tubular ER [13], ER tubules do tethering proteins could act as a zipper support a contractile mechanism for persist at mitochondrial contact sites in to constrict the mitochondrion, the mitochondrial fission. Nat. Struct. Mol. Biol. 18, 20–26. mutant yeast cells [1]. Thus, it appears cytoskeleton might be involved, or the 7. James, D.I., Parone, P.A., Mattenberger, Y., that mitochondria can aid the ER in activity of proteins in the mitochondrial and Martinou, J.C. (2003). hFis1, a novel component of the mammalian mitochondrial generating tubular membranes when inner membrane could be important. fission machinery. J. Biol. Chem. 278, endogenous ER membrane shaping Are the ER contacts essential for 36373–36379. Current Biology Vol 21 No 22 R924

8. Gandre-Babbe, S., and van der Bliek, A.M. contacts with the endoplasmic reticulum as 18. Csordas, G., Renken, C., Varnai, P., Walter, L., (2008). The novel tail-anchored membrane determinants of mitochondrial Ca2+ responses. Weaver, D., Buttle, K.F., Balla, T., protein Mff controls mitochondrial and Science 280, 1763–1766. Mannella, C.A., and Hajnoczky, G. (2006). peroxisomal fission in mammalian cells. Mol. 13. Voeltz, G.K., Prinz, W.A., Shibata, Y., Rist, J.M., Structural and functional features and Biol. Cell 19, 2402–2412. and Rapoport, T.A. (2006). A class of membrane significance of the physical linkage between 9. Otera, H., Wang, C., Cleland, M.M., proteins shaping the tubular endoplasmic ER and mitochondria. J. Cell Biol. 174, Setoguchi, K., Yokota, S., Youle, R.J., and reticulum. Cell 124, 573–586. 915–921. Mihara, K. (2010). Mff is an essential factor for 14. Pitts, K.R., Yoon, Y., Krueger, E.W., and 19. Szabadkai, G., Bianchi, K., Varnai, P., De mitochondrial recruitment of Drp1 during McNiven, M.A. (1999). The dynamin-like protein Stefani, D., Wieckowski, M.R., Cavagna, D., mitochondrial fission in mammalian cells. J. DLP1 is essential for normal distribution and Nagy, A.I., Balla, T., and Rizzuto, R. (2006). Cell Biol. 191, 1141–1158. morphology of the endoplasmic reticulum and Chaperone-mediated coupling of endoplasmic 10. Legesse-Miller, A., Massol, R.H., and mitochondria in mammalian cells. Mol. Biol. reticulum and mitochondrial Ca2+ channels. J. Kirchhausen, T. (2003). Constriction and Cell 10, 4403–4417. Cell Biol. 175, 901–911. Dnm1p recruitment are distinct processes in 15. Martins de Brito, O., and Scorrano, L. (2010). An 20. Martins de Brito, O., and Scorrano, L. (2008). mitochondrial fission. Mol. Biol. Cell 14, intimate liaison: spatial organization of the Mitofusin 2 tethers endoplasmic reticulum to 1953–1963. endoplasmic reticulum-mitochondria mitochondria. Nature 456, 605–610. 11. Achleitner, G., Gaigg, B., Krasser, A., relationship. EMBO J. 29, 2715–2723. Kainersdorfer, E., Kohlwein, S.D., Perktold, A., 16. Kornmann, B., Currie, E., Collins, S.R., Zellnig, G., and Daum, G. (1999). Association Schuldiner, M., Nunnari, J., Weissman, J.S., ¨ between the endoplasmic reticulum and and Walter, P. (2009). An ER-mitochondria Institut fu¨r Zellbiologie, Universitat Bayreuth, mitochondria of yeast facilitates interorganelle tethering complex revealed by a synthetic 95440 Bayreuth, Germany. transport of phospholipids through membrane biology screen. Science 325, 477–481. E-mail: [email protected] contact. Eur. J. Biochem. 264, 545–553. 17. Merz, S., Hammermeister, M., Altmann, K., 12. Rizzuto, R., Pinton, P., Carrington, W., Du¨rr, M., and Westermann, B. (2007). Molecular Fay, F.S., Fogarty, K.E., Lifshitz, L.M., machinery of mitochondrial dynamics in yeast. Tuft, R.A., and Pozzan, T. (1998). Close Biol. Chem. 388, 917–926. DOI: 10.1016/j.cub.2011.10.010

Feedback Modulation: A Window into order to produce intelligent and sophisticated compensation to Cortical Function disturbances. The study uses a combination of neural recordings from primates and TMS studies in man A recent study demonstrates involvement of primary motor cortex in to support this finding. task-dependent modulation of rapid feedback responses; cortical neurons Pruszynski et al. [15] used a robotic resolve locally ambiguous sensory information, producing sophisticated interface to apply perturbations to the responses to disturbances. arm consisting of different combinations of elbow and shoulder David W. Franklin task-dependent voluntary responses joint torques. This requires each joint to and Daniel M. Wolpert [8]. This provides further support for compensate for the torque it optimal feedback control and suggests experiences. The design of the study An emerging theory in sensorimotor that the control system sets a unified set exploited a fundamental neuroscience, termed optimal of gains that act both on the involuntary biomechanical property of a multi-joint feedback control, postulates that and voluntary systems, suggesting limb: that is, many different complex actions result from the the same neural circuitry may underlie combinations of externally applied joint intelligent modulation of sensory both forms of control and blurring the torques can give rise to identical local feedback gains [1–3]. That is, skilful distinction between them [3]. motion at a single joint. Therefore, it is movements are formulated by the The long-latency feedback response not possible to disambiguate the sensorimotor control system by is known to involve cortical pathways appropriate response at the shoulder specifying time-varying feedback gains [9,10]. Moreover, recent transcranial joint based only on shoulder motion on states of the body (for example, the magnetic stimulation (TMS) studies information (or only on elbow motion limb position and velocity). The ensuing have shown that stimulation of primary information). In other words, shoulder movement arises from the interaction motor cortex can change the motion alone provides highly of these feedback gains with the task-dependent modulation of the ambiguous information as to applied mechanics of the musculoskeletal long-latency feedback response shoulder torques, which can only be system, neural noise and disturbances [11,12]. As primary motor cortex is also disambiguated by also considering from the environment. implicated in voluntary control [13,14], elbow motion. Therefore, to Optimal feedback control has been this is a prime candidate for the compensate for the perturbation, supported by several studies showing integrated control of both voluntary feedback responses need to take into that feedback responses are clearly and feedback control. account information about motion at modulated throughout movement [4] A recent paper [15] reports evidence both the shoulder and elbow joints [16]. and depend on the task being that primary motor cortex neurons The research specifically investigated performed [5–7]. In addition, actively function in the task-dependent neurons that demonstrate primarily perturbations invoke involuntary modulation of feedback pathways. shoulder tuning in feedforward feedback responses — the long latency Specifically, this new work shows that (voluntary) control tasks, in other words stretch reflex — that approximate, in primary motor cortex neurons resolve have neural tuning indistinguishable direction and magnitude, the later ambiguous local motion at the joints in from single joint shoulder muscles.