Polo-Like Kinases in the Nervous System

Polo-like kinases in the nervous system

Daniel P Seeburg1, Daniel Pak1 and Morgan Sheng*,1

1The Picower Center for Learning and Memory, RIKEN-MIT Neuroscience Research Center, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA

Polo like kinases (Plks) are key regulators of the cell Intriguingly, neuronal Plks are regulated by synaptic cycle, but little is known about their functions in activity and can interact with specific synaptic proteins, postmitotic cells such as neurons. Recent findings indicate resulting in loss of synapses. In this review, we briefly that Plk2 and Plk3are dynamically regulated in neurons summarize the roles of Plks in the cell cycle and then by synaptic activity at the mRNA and protein levels. In discuss developments on neuronal Plks and their COS cells, Plk2 and Plk3interact with spine-associated implications for the physiological role of these proteins Rap guanosine triphosphatase-activating protein (SPAR), in the nervous system. a regulator of actin dynamics and dendritic spine The Plks are characterized by a conserved architecture morphology, leading to its degradation through the consisting of an N-terminal kinase domain and a C- ubiquitin–proteasome system. Induction of Plk2 in terminal Polo box domain. The latter binds to phos- hippocampal neurons eliminates SPAR protein, depletes phoserine/threonine motifs and is believed to be a core postsynaptic scaffolding molecule (PSD-95), and important for the functional regulation of the protein causes loss of mature dendritic spines and synapses. These by targeting the kinase to specific subcellular locations findings implicate neuronal Plks as mediators of activity- and substrates (Lee et al., 1998; May et al., 2002; Elia dependent change in molecular composition and morphol- et al., 2003a, b; Ma et al., 2003b; Reynolds and Ohkura, ogy of synapses. Induction of Plks might provide a 2003; Lowery et al., 2004). Flies, budding yeast, and homeostatic mechanism for global dampening of synaptic fission yeast contain a single Plk, referred to as Polo, strength following heightened neuronal activity (‘synaptic Cdc5p, and Plo1, respectively. In mammals, frogs, and scaling’). Synapse-specific actions of induced Plks are also worms, there are three Plks, denoted Plk1, Plk2, and possible, particularly in light of the discovery of Plk3. (Plk in Xenopus laevis is also referred to as Plx. phosphoserine/threonine peptide motifs as binding targets Plk2 and Plk3 are also known as SNK/hSNK and FNK/ of the polo box domain, which could allow for ‘priming’ Prk in mice/humans, respectively.) Plk1 is thought to be phosphorylation by upstream kinases that could ‘tag’ Plk the functional homolog of Drosophila Polo and, substrates only in specific synapses. together with Cdc5p, is the most extensively studied of Oncogene (2005) 24, 292–298. doi:10.1038/sj.onc.1208277 the Plks. Plk1 plays a critical role in the timing of mitotic entry and exit through the activation of Cdc25C Keywords: SNK; Plk2; SPAR; immediate-early genes; and Cdc2-cyclin B at the G2–M transition (Roshak spines et al., 2000; Toyoshima-Morimoto et al., 2001; Toyoshi- ma-Morimoto et al., 2002) and through activation of the anaphase promoting complex (APC) in mitosis (Kotani et al., 1998; Golan et al., 2002; but see: Kraft et al., 2003). Plk1 also regulates the mechanics of mitotic Introduction processes such as centrosome assembly and separation (Lane and Nigg, 1996; do Carmo Avides et al., 2001; The study of Polo-like kinases (Plks) has focused Dai et al., 2002; Blagden and Glover, 2003), chromo- primarily on the critical role of these proteins in the some and sister chromatid separation during meiosis I cell cycle. Named after their first member in Drosophila and mitosis, respectively (Sumara et al., 2002; Clyne melanogaster (Polo) (Sunkel and Glover, 1988; Llama- et al., 2003; Lee and Amon, 2003), fragmentation of zares et al., 1991), this family of serine/threonine kinases Golgi membranes (Carmena et al., 1998; Song and Lee, has emerged as a key regulator during all stages of 2001; Sutterlin et al., 2001; Colanzi et al., 2003), and mitosis and the cell cycle checkpoint response to cytokinesis (Carmena et al., 1998; Song and Lee, 2001; genotoxic stress (Glover et al., 1998; Nigg, 1998; Xie Neef et al., 2003). et al., 2002). Despite their well-characterized roles in Plk3 is less well understood, although recent investi- dividing cells, recent studies suggest that Plks have roles gations have revealed diverse roles, both in the cell cycle in terminally differentiated cells of the nervous system. and beyond. Like Plk1, Plk3 activates Cdc25C at the onset of mitosis (Ouyang et al., 1997; Ouyang et al., *Correspondence: M Sheng, The Picower Center for Learning and 1999; Bahassi el et al., 2004), participates in breakdown Memory, MIT, 77 Massachusetts Avenue (E18-215), Cambridge, MA of the Golgi (Ruan et al., 2004; Xie et al., 2004), and is 02139, USA; E-mail: [email protected] important for cytokinesis (Conn et al., 2000). In Plks in the nervous system DP Seeburg et al 293 addition, Plk3 regulates microtubule dynamics and differential screens for activity-regulated genes, it is centrosomal function (Wang et al., 2002), and has been estimated that somewhere between 15 and 300 of the reported to function in cellular adhesion (Holtrich et al., thousands of genes expressed in the nervous system are 2000). Following genotoxic stress, Plk3 is activated by rapidly regulated by activity (Hevroni et al., 1998; Chk2 and helps to mediate the stress response, at least in Lanahan and Worley, 1998; Nedivi, 1999). Activity- part by activating p53 (Xie et al., 2001; Bahassi el et al., induced gene expression is believed to be critical for 2002; Xie et al., 2002). In contrast, Plk1 is inhibited formation of long-term synaptic changes (synaptic following DNA damage (Smits et al., 2000; van Vugt plasticity) in the brain, which might underlie learning et al., 2001) and its mRNA expression is repressed by and memory. Based on the timescale over which BRCA-1 (Ree et al., 2003) and p53 (Kho et al., 2004). synaptic change persists, several forms of synaptic Plk2 is the least studied of the Plks. Unlike Plk1 and plasticity can be delineated, each with different under- Plk3, Plk2 seems to lack a prominent role in the cell lying molecular mechanisms and dependence on gene cycle. Plk2 is expressed in the brain, but is notably expression. Short-term synaptic alterations are mediated absent from proliferating tissue such as thymus, liver, or largely by post-translational modification and regula- intestine (Simmons et al., 1992). Moreover, Plk2 was not tion of existing proteins and are thus independent of detected in nocodazole-treated cells arrested at M phase, new protein synthesis (Izquierdo et al., 2002). However, but was restricted to G1, indicating that Plk2 likely does for long-term synaptic changes to take place, new gene not function during mitosis (Ma et al., 2003b). Its transcription and protein synthesis are required (e.g. expression during G1, however, implicates a role for Frey et al., 1988; Steward and Schuman, 2001; Bozon Plk2 in the cell cycle, and Plk2À/À fibroblasts grew slower et al., 2003). Thus, the expression profile of neuronal in culture and showed delayed entry into S phase (Ma Plks would make them well suited to participate in et al., 2003a). Plk2À/À mice, although smaller at birth, longer lasting forms of synaptic plasticity. had similar postnatal growth rates compared to The time course of activity-dependent Plk induction controls, consistent with a physiological role in the cell was studied in the brains of rats following drug-induced cycle restricted to the embryonic period (Ma et al., seizures. After 1 h, the mRNA levels of Plk2 and Plk3 2003a). were increased B1.6-fold. The fold-induction was Beyond their key role in cell division, Plks are also similar at 4 h, and mRNA levels returned to baseline found in postmitotic cells such as neurons, but the by 10 h. Similarly, protein levels of Plk2 and -3 were neuronal functions of Plks are poorly understood. potently induced and enriched in somata and dendrites Interestingly, several cell cycle regulators are now of activated neurons (Kauselmann et al., 1999). Elec- known to have additional activities in neurons. One trical stimulation sufficient to induce long-term poten- example is the APC, a multisubunit complex with E3 tiation (LTP) in the hippocampus, a brain region critical ubiquitin-ligase activity that coordinates cell cycle for learning and memory, also induced Plk2 and Plk3 transitions, including exit from mitosis (Morgan, 1999; mRNAs. On the other hand, low frequency electrical Harper et al., 2002). Activity of the APC is stimulated in stimulation failed to induce Plk2 or Plk3 and did not early mitosis by the regulatory protein Cdc20 and in late change synaptic strength (Kauselmann et al., 1999). mitosis/G1 by Cdh1. Intriguingly, Cdh1 and core Thus, a threshold of synaptic activation is required to components of the APC are also expressed in post- upregulate expression of Plk2 and -3. mitotic neurons (Gieffers et al., 1999; Peters, 2002), Based on pharmacological inhibition experiments, a where the Cdh1–APC has recently been shown to play a number of signaling proteins are required for the role in axonal growth and patterning in the developing induction of Plk2 in neurons. Thus, antagonists of L- brain (Konishi et al., 2004). Similarly, Aurora kinases type voltage-gated calcium channels (VGCCs), or that are involved in chromosome segregation and blockers of postsynaptic glutamate receptors (NMDA cytokinesis during mitosis (Glover et al., 1995; Terada receptors and AMPA receptors), were sufficient to et al., 1998; Blagden and Glover, 2003) have now been prevent activity-induced expression of Plk2 (Pak and shown to phosphorylate and activate cytoplasmic Sheng, 2003). In addition, Plk2 induction required the polyadenylation element-binding protein-1 (CPEB-1) calcium–calmodulin-sensitive protein phosphatase PP2B in neurons and thereby drive polyadenylation-depen- (also called calcineurin (CaN)) (Pak and Sheng, 2003). dent translation at synaptic sites (Huang et al., 2002; These findings are consistent with a model in which Theis et al., 2003). Taken together, these studies suggest calcium entry through NMDA receptors and/or a broad role for cell cycle proteins in differentiated cells VGCCs, which are activated by synaptic activity, of the nervous system. The remainder of this review will stimulates CaN, leading to transcriptional induction of discuss the neuronal functions of Plks. Plk2 (Figure 3, Pak and Sheng, 2003). CaN can regulate transcription in neurons by influencing a number of transcription factors. For Activity-induced expression of Plks in the brain example, CaN causes inactivation of cAMP response element-binding protein (CREB), most likely through Of the three known Plks, only Plk2 and Plk3 are protein phosphatase PP1 (Hagiwara et al., 1992; Bito expressed in the adult brain (Kauselmann et al., 1999). et al., 1996). More pertinently, CaN can activate the Notably, the mRNA and protein levels of these kinases transcription factor NFATc4 through dephosphoryla- are highly elevated by synaptic activity. Based on tion and unmasking of nuclear localization signals

Oncogene Plks in the nervous system DP Seeburg et al 294 (Graef et al., 1999). Recently, mRNA levels of a number most excitatory synapses are formed (Hering and Sheng, of genes were shown to be controlled by CaN by 2001). Within spines, SPAR forms a complex with the differential expression profiling of cerebellar granule postsynaptic scaffolding protein PSD-95 and NMDA cells in the presence or absence of CaN inhibitors receptors (Pak et al., 2001; Roy et al., 2002). SPAR (Kramer et al., 2003), although Plks did not show up in seems to function to promote the growth of dendritic this screen. spines, at least in part by inhibiting Rap (Pak et al., Once induced by activity, Plk2 seems to negatively 2001), a small GTPase involved in the regulation of regulate its own expression at the protein level, probably actin dynamics (McLeod et al., 2004). through autophosphorylation and subsequent degrada- In COS cells, coexpression of Plk2 and SPAR results tion via the ubiquitin–proteasome system (Figure 1). in phosphorylation, ubiquitination, and degradation of Thus, proteasome inhibitors strongly elevate Plk2 SPAR, and Plk3 causes SPAR degradation as well. Plk2 protein levels, even in unstimulated neurons (Pak and kinase activity is necessary for SPAR degradation but Sheng, 2003). Such a mechanism would shorten the half- not for the interaction between Plk2 and SPAR, which is life of active Plk2 and limit the duration of Plk2 protein mediated by the C-terminus containing the polo box induction following synaptic stimulation. domain (Figure 1, Pak and Sheng, 2003). Analogously, Kinase activity of Plk2 is inhibited in the presence of following phosphorylation by Plk1, somatic Wee-1 is the calcium and integrin-binding protein (CIB) (Ma ubiquitinated by the F-box protein b-transducin repeat- et al., 2003b). Consistent with its possible role as a containing protein (b-TRCP) and degraded at the onset calcium-dependent regulator of Plk2, the sequence of of mitosis (Watanabe et al., 2004). The E3 ubiquitin CIB is homologous to several members of the helix– ligase responsible for ubiquitination of SPAR is loop–helix ‘EF-hand’ calcium-binding protein family, unknown. which includes CaN B and calmodulin that are known What is the effect of Plk2 expression in neurons? After to modulate the activity of calcium-dependent phospha- induction by synaptic stimulation in cultured hippo- tases and kinases, respectively. campal neurons, endogenous Plk2 protein accumulates mainly in the cell body and proximal dendrites, where it is enriched in dendritic spines (Pak and Sheng, 2003). Plk2 leads to degradation of a spine-associated protein Normally, SPAR and PSD-95 are concentrated in and remodeling of synapses synaptic clusters associated with spines along the entire length of dendrites, but after induction of Plk2, these A breakthrough in the neuronal function of Plk2/3 came proteins are lost from the same regions where Plk2 is with the discovery of a specific interaction between a present. Thus, there are complementary gradients of postsynaptic Rap guanosine triphosphatase activating distribution of Plk2 and SPAR/PSD-95 immunoreactiv- protein (RapGAP) known as SPAR (spine-associated ity in dendrites of activated neurons. Exogenous Plk2 RapGAP) and the C-terminal region of Plk2 containing introduced into neurons by viral infection accumulates the Polo box domain (Pak and Sheng, 2003). Also an to a higher level and is less restricted to the proximal actin-binding protein, SPAR is enriched in dendritic somatodendritic compartments, but nevertheless, the spines, specialized protrusions of dendrites on which magnitude of effect on loss of SPAR and PSD-95 clusters shows a proximal-to-distal gradient (Figure 2, Pak and Sheng, 2003). The loss of SPAR and PSD-95 clusters is correlated with the depletion of mature dendritic spines and reduced density of synapses on affected dendrites (Pak and Sheng, 2003). Interestingly, there is a corresponding increase in thin dendritic protrusions that resemble filopodia, which are generally believed to be the exploratory precursors of spines (Hering and Sheng, 2001). Dominant-negative SPAR constructs that lack Rap- GAP activity also lead to loss of mature spines and an increase in the number of long, thin dendritic protrusions (Pak et al., 2001). Thus, one mechanism by which activity-induced expression of Plk2 could lead to synapse loss and increased filopodia-like protrusions is through the degradation of SPAR and resulting disin- Figure 1 Plk2 phosphorylates SPAR causing its ubiquitination hibition of the actin regulator Rap. Consistent with this and degradation. Before binding, the polo box and kinase domains idea, overexpression of constitutively active Rap2 of Plk2 interact intramolecularly with mutual inhibition of function mutant in neurons leads to a similar spine phenotype (bottom, left). After binding to SPAR via the polo box domain, the characterized by irregular thin protrusions (DP, unpub- kinase domain is liberated and phosphorylates SPAR and itself via autophosphorylation (top, center). This leads to ubiquitination and lished observations). degradation of SPAR and Plk2 (bottom, right). P, phosphate SPAR is certainly not the only substrate of Plk2 in group; SPAR, spine-associated RapGAP neurons, and degradation of SPAR is unlikely to be the

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Figure 2 Plk2 induces loss of the spine-associated protein PSD-95. Hippocampal cultures were infected at days in vitro (DIV) 18 to DIV 21 with Sindbis virus expressing Plk2 and double stained for exogenous Plk2 (red) and endogenous PSD-95 (green), as indicated, with merged image shown in color. SPAR shows a similar pattern of immunoreactivity as PSD-95 under the same conditions (data not shown) sole mechanism by which Plk2 induction leads to of postsynaptic AMPA receptors, but the molecular remodeling of synapses and spines. Although it is likely mechanisms are still unclear (Turrigiano and Nelson, to be a secondary effect of Plk2 activity, the depletion of 2004). The activity-dependent expression of Plk2, the PSD-95 that accompanies loss of SPAR could also timescale of neuronal Plk2 induction (hours), the contribute to elimination of mature spines and synapses. widespread reach of induced Plk2 protein (i.e. appar- PSD-95 is a key postsynaptic scaffolding molecule ently not targeted to small specific subsets of synapses), important for morphological growth of spines and and the negative effect of activated Plk2 on synapses and functional maturation of synapses (El-Husseini et al., spines together raise the possibility that neuronal Plks 2000; Kim and Sheng, 2004). Thus, while the precise contribute to the mechanisms of global synaptic home- mechanism by which Plk2 induction leads to disman- ostasis (Figure 3a). tling of synapses and spines is uncertain, the regulation It remains possible, however, that the activity of Plk2, of Plk2 expression in neurons provides a powerful or the accessibility of its substrates, can be regulated in a means to remodel synapses following neuronal activity. local synapse-specific manner. In particular, as will be discussed below, the recent discovery of phosphoserine/ threonine peptide motifs as the binding targets of the Global vs local synaptic modifications polo box domain (Elia et al., 2003a, b) allows for the possibility of ‘priming’ phosphorylation by upstream A functional corollary of loss of synapses due to Plk2 kinases that could ‘tag’ Plk substrates only in specific should be the weakening of synaptic transmission onto synapses (Figure 3b). Ultimately, it is still a matter of those neurons. Activity-driven induction of Plk2 thus speculation whether neuronal Plks participate in global presents an attractive homeostatic mechanism for homeostatic plasticity mechanisms or in local synaptic stabilizing the excitability of neurons following heigh- change. Electrophysiological studies and specific loss-of- tened synaptic input (Burrone and Murthy, 2003; function genetic experiments will be required to address Turrigiano and Nelson, 2004). Local changes in synaptic the role of neuronal Plks in synaptic plasticity more strength, arising from positively correlated activity directly. between pre- and postsynaptic neurons, is thought to be important for long-term memory storage (Bi and Poo, 2001). Without homeostatic mechanisms in place, Learning from mitotic Plks however, such correlation-based plasticity can lead to unstable excitability of the cell. For example, when a The multiplicity of Plk substrates in the cell cycle particular synaptic input is potentiated, it becomes raises the possibility that neuronal Plks could have easier for that input to drive the postsynaptic cell to fire, additional substrates besides SPAR. During mitosis which begets further potentiation, eventually causing alone, Plks have been shown to interact with and ‘runaway’ excitation of the postsynaptic neuron (Miller, phosphorylate a diverse set of proteins, including 1996). Homeostatic mechanisms ensure that the excit- BRCA2 (Lee et al., 2004), cyclin B (Toyoshima- ability of a cell as a whole remains within a certain Morimoto et al., 2001; Yuan et al., 2002), the mitotic range, even though a specific subset of synapses may be kinesin-like protein MKLP2 (Neef et al., 2003), and modified up or down. the cdk1 phosphatase Cdc25C (Roshak et al., 2000; Mechanistically, homeostatic regulation is thought to Bahassi el et al., 2004). Of note, the polo box domain occur through multiplicative changes in the strength of was found to be critical in mediating the interaction all (or most) synapses (‘synaptic scaling’), take place in all cases where it was tested (Lin et al., 2000; over a prolonged time course (hours to days), and retain Sutterlin et al., 2001; Yarm, 2002; Elia et al., 2003a, b; the relative strengths between synapses (Turrigiano and Neef et al., 2003; Zhou et al., 2003; Litvak et al., 2004; Nelson, 2000; Turrigiano and Nelson, 2004). The best- Yoo et al., 2004). characterized means of synaptic scaling is alteration of The polo box domain, which contains two conserved postsynaptic excitability through changing the amount polo boxes, their intervening sequence, and a short

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Figure 3 Model for Plk2 induction and global vs synapse-specific function of induced protein. Calcium influx through NMDA and/or VGCCs after synaptic activity activates CaN, which causes induction of Plk2 mRNA and protein. (a) Induced Plk2 acts globally to bind to and cause degradation of SPAR. This could provide a homeostatic mechanism to broadly depress synaptic strength following heightened activity at a subset of synapses. (b) Induced Plk2 is ‘captured’ specifically at spines ‘tagged’ by activity-induced phosphorylation of SPAR. Such a tag could direct Plk2 to a subset of synapses despite ‘nonspecific’ induction in the cell body. Ca2 þ , calcium; VGCC, voltage-gated calcium channel; CaN, calcineurin; SPAR, spine-associated RapGAP; NMDAR, NMDA receptor; AMPAR, AMPA receptor; P, phosphate group

stretch of linker sequence between the kinase domain completion of cytokinesis and further phosphorylation and the first polo box, is critical for correct localization of Claspin by Plk1, respectively. and function of Plks (for a review, see Lowery et al., It will be interesting to see if neuronal Plks behave 2004). Mutation of the polo box domain in mammalian similarly. Priming phosphorylation of Plk2 targets (e.g. Plk1 prevented its correct localization and its ability to SPAR) within their Plk-binding motif could allow for complement a Cdc5 mutant in budding yeast (Lee et al., synapse-specific recruitment of Plk2 in spite of ‘non- 1998). Overexpression of the polo box domain by itself specific’ induction of the mRNA and protein in the cell led to a dominant-negative cell cycle arrest in pre- body. Such a mechanism would be analogous to what anaphase in mammalian cells (Seong et al., 2002) and has been proposed by the ‘synaptic-tagging’ hypothesis, prevented completion of cytokinesis in budding yeast a model put forward to address the question of how new (Song and Lee, 2001). gene products required for long-term synaptic change Recently, an optimal consensus binding motif for the are delivered from the nucleus to the few activated PBD was determined with the sequence Ser-[pSer/pThr]- synapses within the vast dendritic tree that require them [Pro/X] (Elia et al., 2003a; Elia et al., 2003b). This raises (for a review, see Martin, 2002; Martin and Kosik, the intriguing possibility that binding of the Plk-PBD 2002). According to this model, new protein products might require prior phosphorylation of Plk substrates by are delivered throughout the entire cell, but act a ‘priming’ proline-directed serine–threonine kinase specifically only at those synapses that have been (such as MAP kinases or CDKs). Although such ‘tagged’ by synaptic activity. Despite strong evidence priming events are yet to be investigated in most cases, that some type of synaptic tagging occurs, both the several recent studies have found results consistent with identity of the ‘tag’ and the mechanism of subsequent this idea. In one instance, it was shown that prior ‘capture’ of newly synthesized proteins have remained phosphorylation of cyclin B by Erk2 greatly enhanced elusive (Martin and Kosik, 2002). cyclin B phosphorylation by Plk1 (Yuan et al., 2002). More recently, it was found that phosphorylation of the peripheral Golgi protein Nir2 by Cdk1 (Litvak et al., Conclusions 2004) or of the DNA replication checkpoint mediator Claspin in Xenopus egg extracts (Yoo et al., 2004) Recent findings have revealed the regulated expression created docking sites for Plk1 that were required for and a cell biological function of Plks in neurons. Plk2

Oncogene Plks in the nervous system DP Seeburg et al 297 and Plk3 are induced by neural activity and show The study of Plk2/SNK has lagged behind Plk1 and promise as possible mediators of synaptic remodeling. Plk3, primarily because it has a limited role in the cell Many questions remain to be addressed, however. For cycle. Analogous to CDK5 (a cyclin-dependent kinase example, what are the other substrates of neuronal homolog that is abundant in neurons), Plk2 might turn Plks besides SPAR? And how are they regulated by out to be an ‘aberrant’ family member that has been co- Plks? Can degradation of SPAR fully account for the opted by postmitotic cells to function in entirely spine phenotype seen with induction of Plks? Do different contexts. It remains to be seen whether Plks Plks have significant roles in the presynaptic terminal have as broad a role in the nervous system as they do in or even outside of the synapse? What are the relative the cell cycle. Given the tantalizing evidence so far, contributions of Plk2 and Plk3? Are Plks involved in elucidating the functions of Plks in the nervous system global or local synaptic plasticity? And what is their should be richly rewarding. significance for brain development, function, and behavior? The molecular study of Plks in neurons can Acknowledgements benefit from the rich understanding of Plk actions We thank Sashank Reddy for helpful comments on the in the cell cycle; but the neurobiological significance of manuscript and Jacek Jaworski as well as Casper Hoogenraad Plks cannot be simply extrapolated from studies of for comments on the figures. Morgan Sheng is an Investigator dividing cells. of the Howard Hughes Medical Institute.

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