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Review Polarity Proteins in Axon Specification and Synaptogenesis Developmental Cell, Vol. 8, 803–816, June, 2005, Copyright ©2005 by Elsevier Inc. DOI 10.1016/j.devcel.2005.05.007 Polarity Proteins in Axon Review Specification and Synaptogenesis Giselle R. Wiggin,1,3 James P. Fawcett,1,3 which is also implicated in the regulation of polarity and Tony Pawson1,2,* (Guo and Kemphues, 1995; Watts et al., 2000; Izumi et 1Samuel Lunenfeld Research Institute al., 1998). PAR-2 is a RING finger protein (Levitan et al., Mount Sinai Hospital 1994), PAR-5 a 14-3-3 protein, which recognizes phos- 600 University Avenue phorylated serine/threonine motifs (Morton et al., 2002), Toronto, Ontario M5G 1X5 and both PAR-3 and PAR-6 are PDZ-domain-containing Canada proteins (Etemad-Moghadam et al., 1995; Hung and 2 Department of Medical Genetics and Microbiology Kemphues, 1999). University of Toronto Experiments employing the mammalian and Dro- 1 Kings College Circle sophila orthologs of these C. elegans PAR proteins Toronto, Ontario M5S 1A8 have shown that they can directly interact with one an- Canada other to form larger multiprotein complexes. For exam- ple, PAR-6 associates with aPKC through its N-terminal PB1 domain, with GTP bound Cdc42 or Rac through The neuron is a prime example of a highly polarized a partial CRIB motif, and with PAR-3 through its PDZ cell. It is becoming clear that conserved protein com- domain, to form a subapical complex in epithelial cells plexes, which have been shown to regulate polarity (Hung and Kemphues, 1999; Joberty et al., 2000; Lin et in such diverse systems as the C. elegans zygote and al., 2000; Garrard et al., 2003). mammalian epithelia, are also required for neuronal In addition to PAR-3, PAR-6 and aPKC also associate polarization. This review considers the role of these with the tumor-suppressor protein Lethal giant larvae polarity proteins in axon specification and synapto- (Lgl, a large protein containing 14 WD40 repeats), lead- genesis. ing to Lgl phosphorylation and functional inactivation (Plant et al., 2003; Betschinger et al., 2003; Yamanaka Introduction et al., 2003). PAR-6 can also bind the MAGUK protein The ability of cells to polarize is critical for complex Pals1, which is apically localized in epithelial cells (Hurd biological activities, such as the organization of the et al., 2003a; Wang et al., 2004). nervous system. Indeed, neurons are among the best These dynamic PAR-6/aPKC complexes therefore examples of a highly differentiated and polarized cell provide a biochemical link between distinct sets of po- type, typically extending a long thin axon, which is en- larity proteins that localize along an apical-basal axis in gineered to propagate signals, and several shorter and epithelial cells. These include the apical Crumbs/Pals/ thicker dendrites, which are designed to receive signal Patj complex, the PAR-3/PAR-6/aPKC complex, and inputs. The transfer of information from a neuron to its the basolateral Scribble/Lgl/Dlg complex (Bilder, 2004; target occurs at the synapse, which are composed of Macara, 2004). Consistent with the biochemical data, specialized pre- and postsynaptic structures. The pre- genetic analyses in Drosophila indicate that the PAR-3, synaptic terminal stores vesicles, which upon activa- Crumbs, and Scribble complexes have mutually inter- tion release neurotransmitters into the synaptic space, dependent functions (Tanentzapf and Tepass, 2003; where they act on postsynaptic receptors. The asym- Bilder et al., 2003). For example, the apical localization metric localization of proteins within the axon, dendrite, of the Crumbs/Pals/Patj complex is dependent on the and synapse is essential for a neuron to establish its PAR-3/PAR-6/aPKC polarity cassette (Nam and Choi, functional architecture. 2003; Hurd et al., 2003a; Tanentzapf and Tepass, 2003). A wealth of recent data has identified a number of The Crumbs complex in turn antagonizes the Scribble/ gene products that have the capacity to impose cellular Lgl/Dlg complex by regulating the size of the apical do- asymmetry, in part through their ability to form dynamic main and maintaining the position of the PAR-3/PAR-6/ multiprotein complexes. Here we will consider the no- aPKC complex (Tanentzapf and Tepass, 2003; Bilder et tion that such polarity proteins participate in axon specifi- al., 2003). Together these polarity complexes define cation, growth, and synaptogenesis, in part through sig- specific apical-basolateral domains of epithelial cells naling to the actin and microtubule cytoskeletons. and the formation of specialized cell junctions. It is therefore pertinent to consider whether similar forces Polarity Complexes are at work in establishing polarity and specialization in The prototypic PAR (for partitioning-defective) genes neuronal cells. were identified in C. elegans for their roles in directing asymmetric cell division during early development Axon Specification (Cowan and Hyman, 2004), and they encode proteins The initial event in establishing a polarized neuron is with catalytic and interaction domains characteristic of the specification of a single axon. How does one, and cellular signaling. PAR-1 and PAR-4 are serine/threo- only one, neurite commit to become an axon, and how nine kinases, as is the atypical protein kinase C (aPKC), do the others remain as dendrites? Both the establish- ment and maintenance of neuronal polarity involve co- *Correspondence: [email protected] ordinated and widespread regulation of the cytoskele- 3 These authors contributed equally to this work. ton and membrane-trafficking machinery. Developmental Cell 804 Figure 1. Localization of PAR-3 and PAR-6 in Axon Development (A) Axon development and localization of PAR-3 and PAR-6. (B) PAR-3 staining (red) in a stage 3 hippo- campal neuron showing localization of PAR-3 to the axon and tips of developing growth cones. MAP-2 staining (yellow/green) is lo- calized to the cell body and dendrites. The establishment of neuronal polarity has been alone to become an axon. An unstable, loose actin studied extensively through the culturing of pyramidal meshwork may therefore allow microtubules to protrude neurons from the rodent hippocampus. This in vitro dif- into distal areas of the growth cone, thereby promoting ferentiation process has been divided into five stages axon elongation (Bradke and Dotti, 1999). Proteins as- (Figure 1A; Dotti et al., 1988). Shortly after plating, neu- sociated with microtubules also influence axon specifi- rons form lamellipodia (stage one). Neurons then ex- cation, including collapsin response mediator protein- tend several short processes called neurites, which 2 (CRMP-2) and tau, which are preferentially associated grow to around 20 ␮m before undergoing a period of with axonal microtubules. extension and retraction (stage 2). Within 24 hr, one of Therefore, the regulation of both the actin and micro- the neurites (the future axon) begins to elongate very tubule networks appears to be a key determinant in rapidly, whereas the others (the future dendrites) un- axon development. The Rho family of GTPases play an dergo little extension (stage 3). After several days, the important role in controlling the actin cytoskeleton and remaining neurites begin to grow and acquire the char- microtubule orientation, and the phosphorylation of acteristics of dendrites (stage 4). The axon and den- microtubule-associated proteins regulates microtubule drites then reach maturation, neurons form synaptic stability and polymerization. Recent evidence places contacts, and spontaneous electrical activity propa- the PAR-3/PAR-6 complex as a potential hub in both of gates throughout the neural network (stage 5). This in these processes. vitro system by no means recapitulates all aspects of neuronal polarization in vivo, where extrinsic signals from the surrounding cellular environment likely play a PAR Proteins and the Rho Family major role in axon and dendrite development. However, of GTPases in the Axon the culturing of hippocampal neurons is a convenient Before the specification of a single axon (stage 2), PAR-3 way to examine some of the intrinsic mechanisms that is localized in the cell body and at the tips of all nascent govern axon specification. processes (Shi et al., 2003; Schwamborn and Puschel, The neurite destined to become an axon shows a 2004; Nishimura et al., 2005). By stage 3, PAR-3 is lost number of particular characteristics prior to formation from dendrites and becomes selectively expressed in of the axon itself. For example, the axon-to-be de- the axon and developing growth cone (Figure 1B; Shi velops a larger growth cone and accumulates a larger et al., 2003). The spatial and temporal expression of number of organelles and a higher concentration of cy- PAR-6 during axon specification is similar to PAR-3, be- tosolic proteins and ribosomes (Fukata et al., 2002a; ing confined to the cell body and the axon by stage Horton and Ehlers, 2003). Since the motility of neurite 3 of development (Shi et al., 2003; Schwamborn and growth cones is a consequence of high actin turnover, Puschel, 2004). By contrast, when overexpressed in it follows that increased actin instability may also be a neurons, PAR-3 and PAR-6 fail to localize correctly, trigger for axonal specification (Bradke and Dotti, leading to defects in polarization (Shi et al., 2003; 1999). Indeed, global application of actin-depolymeriz- Schwamborn and Puschel, 2004; Nishimura et al., ing drugs results in the development of neurons with 2005). Most of these neurons fail to elaborate a single multiple axons, whereas localized cytochalasin D treat- axon, but instead contain two or more neurites of a sim- ment to an individual neurite causes this projection ilar length, which show abnormal microtubule organiza- Review 805 tion and do not express markers of mature axons (Shi have all the features of a mature axon, suggesting that et al., 2003; Nishimura et al., 2005). additional components are necessary for full matura- The Rho family members Rac1 and Cdc42 regulate tion.
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