Septin functions during neuro-development, a yeast perspective

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ScienceDirect Septin functions during neuro-development, a yeast perspective Julien Falk, Leila Boubakar and Vale´rie Castellani Septins, discovered almost half a century ago in yeast, have prominent contributions in a broad range of morphological and functional processes from yeast to human. Septins now emerge as key players of neurodevelopment and more specifically of the mechanisms driving the complex morphological differentiation and compartmentalization of neurons that are fundamental to their function. We review here recent advances in Septin-mediated processes of neuron differentiation, which enlighten similarities and differences between neuron and yeast polarity programs. Address University of Lyon, University of Lyon 1 Claude Bernard Lyon1, NeuroMyoGene Institute, CNRS UMR5310, INSERM U1217, 8 Avenue Rockefeller, Lyon F-69008, France Corresponding author: Castellani, Vale´rie ([email protected])

Current Opinion in Neurobiology 2019, 57:102–109 This review comes from a themed issue on Molecular neuroscience Edited by Yishi Jin and Tim Ryan

https://doi.org/10.1016/j.conb.2019.01.012 0959-4388/ã 2019 Elsevier Ltd. All rights reserved.

Introduction Septins were identified in the early 70s in a genetic screen for mutants with impaired yeast cell division cycle [1] and were named based on their localization at the septum of dividing cells. Septins are represented in most organisms except plants. Yeasts have seven Septins while humans have thirteen, which are classified in four groups. Septins are GTP-binding proteins that oligomerize in proto-filaments. Within proto-filaments, each Septin is predicted to be substitutable by any Septins of the same group, which generates diversity but also redundancy. Septin oligomers usually polymerize into filaments that can assemble into higher order structures (Figure 1a–c) [2,3]. Depending on cell-type and stage, Septins can form filaments of different compositions that organize in different ways. Septins can associate not only with plasmatic and endosomal membranes but also with actin and microtubule cytoskeletons. Septins are involved in cell division, differentiation, migration, or polarization [2,3]. Studies in yeast have Current Opinion in Neurobiology 2019, 57:102–109

brought seminal contributions to the understanding of cell polarization and morphogenesis, and many knowledges were extended to animal cells. Highly complex morphologies and functions of neurons appear so unique and yet many of neuronal features can be found in their basic form in yeast [4] (Figure 1d). Several Septins are expressed in mature and developing neurons and have potential implications in neurological diseases [5–7]. Septins contribution to neurodevelopment has remained unknown for long. First, knock-out (KO) mice of the first neuron-specific Septins (i.e. 3 and 5) exhibited no obvious neurodevelopmental phenotypes [8–10], likely due to the compensations allowed by Septin redundancy. In support, mimicking Septin2 upregulation that occurs in Septin5 KO mice, in cultured neurons transiently depleted for Septin5 could rescue their morphology [8,11]. Second, embryonic lethality of Septin7 or 9 KO mice prevented to study their role during neurodevelopment [12,13]. Nevertheless, acute and conditional genetic perturbations have started to uncover important roles of Septins during neuronal differentiation and physiology.

Control of neuronal progenitor divisions by Septins Septins are critical regulators of cytokinesis in yeast and their contributions to animal cell division is now recognized to be cell-type and context-dependent [14] (Figure 1d). Several Septins were found in neural progenitors and their role during mitosis was only recently uncovered. The first evidence came from a study of progenitors of bristle sensory organs in Drosophila. The sensory organ progenitor (SOP, or pI) cell generates two progenitors, pIIa and pIIb, through planar division. The pIIb divides perpendicularly to the epithelium to generate a third progenitor, pIIIb that will give rise to a neuron and a sheet cell. Septin loss was found to result in failure of cytokinesis of pl planar division. In contrast, it had milder consequences on pllb perpendicular division, only manifested by a delay of cytokinesis. This raised a model whereby, specifically in the context of planar division, Septin provides a contraction force overcoming adherens junctions-mediated mechanical constraints from neighbor cells, needed for completion of cytokinesis [15]. Control of mitosis duration by Septins was also demonstrated in the context of the generation of sensory neurons by neural crest cells (NCCs)-progenitors in chick. NCCs migrate from the dorsal neural tube and coalesce, with www.sciencedirect.com

Septin-mediated neuronal polarity Falk, Boubakar and Castellani 103

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Septins: organization and functions. (a) Septins are composed of a GTPase domain, a polybasic region and a Septin Unique Element (SUE) that is well conserved. N-ter and C-ter domains are variable between members. (b) Organization of Septins families. Each group is composed of several members, at the exception of Septin7. Once assembled, Septin monomers can form a variety of hetero-oligomers. (c) In order to be active, Septins oligomerize in heterodimers and then polymerize into filaments, which allows them to form higher order structures. (d) Similarities in yeast and neuron polarized processes such as cell division, morphogenesis and compartmentalization, in which contributions of Septins have been retained over evolution.

some of them continuing proliferating in the nascent ganglia. Septin loss of function did not block NCCs mitosis in the DRG but resulted in increased mitosis duration. Interestingly, NCCs also failed to divide according to the Hertwig’s rule (or long axis rule) after Septin perturbation, suggesting that Septins contribute to define the division axis in DRG progenitors. Alteration of division axis was indeed observed after Septin knockdown in Drosophila neuroblasts (NB). NBs generate the majority of neurons. Apico-basal neuroblast divisions generate a NB and a ganglion mother cell (GMC). Neuroblasts keep on proliferating, maintaining the same axis of division over many cell cycles. The www.sciencedirect.com

division axis depends on the apically polarized PAR proteins defining the orientation of the mitotic spindle. Interestingly, PAR polarity disappears after mitosis and is re-established before the next one. The maintenance of the division axis orientation was recently demonstrated to depend on the position of the last-born GMC [16]. Septin2 was found to accumulate at the midbody, establishing a mark of the position of the newly generated GMC (Figure 2a). Septin1 or 2 knockdown did not prevent cytokinesis but impaired the ability of NB to set division axis accordingly to last-born GMC [16]. In conclusion, although evidences showing that Septins are required to complete cytokinesis in neural progenitors Current Opinion in Neurobiology 2019, 57:102–109

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Comparison of Septin dynamics and contribution to polarity. (a) Neuroblast division axis defined by PAR polarization (green) is maintained over many cell cycles but has to be reset at each cycle. Septins (blue) localize to the midbody and remain at the membrane contact, which provides a spatial reference for the PAR polarization. (b) Simplified representation of Septin localization during yeast axial budding. Birthmark is shown in green and Septin in blue. (c) Septin dynamics during sensory neuron generation in the dorsal root ganglia. Septin7 accumulates at the positions of retracting progenitor processes and daughter cells make protrusion from these sites. Septin7 accumulates at the midbody, which corresponds to the region where the second process protrudes.

are still lacking, live imaging have started to uncover Septin contributions during mitosis. Interestingly, as in the case of NB, their role in dividing neuronal progenitors closely mirrors that in yeast (Figure 2b).

Control of neuron polarity by Septins Yeast budding is a valuable model for cell polarization. Neurons are morphologically, functionally, and molecularly polarized. Axon-dendrite process emergence subdivides the neurons in distinct morphological compartments. As the neuron matures, processes acquire different morphologies and functions, resulting from specific molecular dynamics and composition. Remarkably, neuronal polarization can take various subtype-dependent routes. Neurons can directly inherit their polarity from progenitors, as in the retina [17]. NCCs, which generate bipolarshaped DRG neurons, bear, before their mitosis, bipolar short processes that are reformed by daughter cells after division. Live monitoring of NCCs revealed that Septin7 marks the position of the progenitor processes during Current Opinion in Neurobiology 2019, 57:102–109

mitotic rounding and that process reform from the Septin-tagged sites. Functional Septin perturbations in NCCs erase this imprint, and processes form at sites different from those of the mother. Thus Septin7 spatially encodes progenitor morphological features for inheritance by the daughter neurons, a conclusion also supported by increase of non-polarized morphologies of early DRG neurons, when Septin functions are impaired [18]. In Drosophila sensory organs, the neuron forms its apical dendrite just after birth at the midbody position. This neuron polarity is thought to be defined by the mitotic cleavage site, with Rho1 and Aurora midbody-enriched proteins persisting after cytokinesis to promote process formation [19]. As they accumulate at the midbody, Septins could also provide some landmarks. Interestingly in DRG neurons, the second process emerges at or close from the Septin7-accumulating midbody [18]. This suggests that Septins could coordinate polarity over the neuronal differentiation program as they do in yeast (Figure 2b,c). Indeed, during axial budding, buds form next to the birthmark left by the preceding cytokinesis. Septins relocalize from the birthmark to the incipient bud www.sciencedirect.com

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site, coupling cell polarization to the polarity established during the previous cell cycle. In other cases, neuronal polarization is preceded by a post-division migration step. In the cerebral cortex, pyramidal neurons migrate radially from deep ventricular region toward more superficial positions and interneurons migrate tangentially to reach the cortex and radially to populate cortical layers. These migrating neurons bear a leading and trailing process that prefigure their polarity [20,21]. Apical radial glia cells give rise to early born neurons and non-polarized intermediate progenitors that generate the majority of pyramidal neurons. Multipolar at birth, these neurons become bipolar by forming their migratory leading and trailing processes. After migration along the radial glia scaffold, the trailing and leading processes transform in axon and dendrite, respectively. Failure in migration resulting from Septin4 and 14 manipulations leads to accumulation of cells which are multipolar, compatible with Septin-mediated coupling between migration and neuronal polarity [22]. In vitro, cortical and hippocampal neurons initially form several equivalent short processes or neurites. Later on, one of them accumulates specific molecules, grows faster and become the axon, the other neurites forming the dendrites. Thus, in vitro pyramidal neurons intrinsically switch from multipolar unpolarized to multipolar polarized stage as they specify a single axon [23,24]. Septins are connected to key molecular pathways found to control axon specification, such as cdc42 regulating Septin localization and PAR3 interacting with Septins [25– 27]. However, in vitro pyramidal neurons succeed to form an axon and several dendrites in absence of Septin4, 14 or 7 [22,28]. Precautions must be taken for conclusions on the lack of Septin contribution these experiments suggest. For example, axon specification might depend on early polarization events that escaped the manipulations due to technical limitations [20,23,29,30]. Septins also contribute to maintenance of axo-dendritic polarity, crucial for neuron functions. Septin9 selectively accumulates in the dendrite proximal domain, from where it controls the selectivity of vesicular trafficking. Septin9 recognizes dendrite-specific KIF1A motor to promote its landing onto dendrite MT while it decreases transport of axonal cargoes using KIF5 motor [31] (Figure 3a). In conclusion, as for cell division, Septins contributions to neuronal polarity are likely context-type and cell-type dependent. Given the range of processes that Septins regulate in yeast, which are mirrored in the differentiating neuron, these contributions are far from being fully unraveled. www.sciencedirect.com

Control of axon elongation and branching by Septins Yeasts can switch from round to filamentous shapes by making chains of elongated buds. Budding yeast can form a mating process in response to pheromone from the mating partner. The mating process elongates, for accuracy tracking of weak pheromone gradient. Septins are present in processes and, functionally contribute to both normal filamentous growth and mating process elongation [32,33] (Figure 1d). Similarly, Septins were shown to control the elongation of processes elaborated by the neurons. Axonal growth and orientation are driven by highly dynamic distal tip, called the growth cone. Several Septins were found to be enriched in neurites and growth cones [34–38] (Figure 1d). Consistently in cultured DRG and pyramidal neurons, Septin4, 5, 6, 7, and 14, were shown to promote axon growth as well as in pyramidal neuron dendrite extension [22,28,34,37] (Figure 3b). In vivo observations of DRG neurons support this role as Septin inhibition, using Borg3 interfering peptide or Septin7 SiRNAs, was found to prevent protrusions from transforming into neurites [18]. Whether this validation also applies to pyramidal neurons is yet unclear [28]. In addition to extension per se, Septins might also control growth orientation as, in Caenorhabditis elegans embryos, axons from ventral nerve cord neurons fail to properly navigate and to form commissures [39]. Furthermore in cultured neurons, Septins are found forming arc or chevron-like structures in the axon and dendrites at the base of branch points neurons [22,28,34,36,37] (Figure 1d). Consistently with this distribution, Septin7 was reported to promote axon branches or collateral formation in DRG and hippocampal neurons [28,34]. In vivo, Septin7 was also found to support collateral formation and extension of cortical axons into the contralateral hemisphere [28]. Other Septins could take part in this process as Septin6 has similar axon collateralinducing effect in cultured DRG neurons and Septin alteration in C. elegans embryos, prevents axons of ventral neurons to form their typical two branches pattern [34,39]. Moreover, several Septins (2, 5, 6, 7, 8, and 11) were described to support dendrite arborization in pyramidal neurons in vitro [11,28,36,38,40,41,42], properties which were confirmed in vivo for Septin7 [28]. Thus overall, Septins appear as key players of the programs controlling neuronal morphologies, controlling length, complexity, and possibly spatial orientation of their processes.

Control of synaptic compartmentalization by Septins During budding, mother and daughter cells are partly insulated from each other and Septins, which accumulate at the mother-bud neck, control bud shape and independence. Analogous compartmentalization is observed Current Opinion in Neurobiology 2019, 57:102–109

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Potential molecular mechanisms underlying Septin functions in neurons. (a) Role of Septin9 (violet) in sorting vesicles destined to dendrites and axons. Septin9 deposited on proximal dendrite microtubules (black) interacts with the motor KIF1A (blue) to facilitate its movement into the dendrites. Septin9 prevents entry of axonal cargoes (KIF5) into the dendrites [31]. (b) Septin7 supports axo-dendritic elongation and microtubule growth. Septin7 could, via its interaction with HDAC (blue) and microtubule (grey acetylated), facilitate microtubule deacetylation (black) and thus promote microtubule dynamics for optimal level of neurite growth. (c) Septin functions at the synapse. In the presynaptic element (grey), Septin5 when present at the active zone can prevent synaptic vesicles (SV) docking to the membrane [53]. Phosphorylated Septin7 relocalizes postsynaptic element (spine), where it orchestrates spine maturation through interaction with PSD95. In addition, Septin7 at the spine neck acts as a diffusion barrier to confine membrane proteins to the spine [44,47]. (d) Septin functions during branching. Septin6 early recruitment to the incipient branch stabilizes Cortactin (violet), which promotes actin (red) polymerization and filopodia formation. Seconds later, Septin7 accumulations at the base of the protrusion increase microtubule unbundling and polymerization ends (+) to support microtubule entry and branch elongation [34].

between the dendritic shaft and the spines [43]. Spines are small protrusions that mature from filopodia-like to mushroom-like shape, forming the post-synaptic elements. Septins (6, 7, and 11) have been found at the base of the spines in cultured neurons [36,38,40,41,44] (Figure 1d). As neurons aged, an increasing number of spines were seen to exhibit Septin accumulation [36,44]. In vivo in the cerebellum, Septin11 could be localized at the neck of dendritic spines from Purkinje cells [41] and biochemical analysis revealed that 9 Septins are present in or associated with the post-synaptic fraction [36,45,46]. Current Opinion in Neurobiology 2019, 57:102–109

While Septins (2, 6, 7, 8, and 11) promote spine protrusion from the dendritic shaft, several of them (6, 7, and 11) were also shown to limit their length [36,38,41,42,44,47]. A detailed analysis of spine dynamics demonstrated that Septin7 is required for dendrites to stabilize spine protrusions and to mature them into mushroom-like structures. These functions depend on shuttling of phosphorylated Septin7 into the spine head where it interacts with and stabilizes PSD95. Blocking phosphorylation leads to decrease spine stability and to increase synaptic contracts at the dendrite shaft, resulting in calcium transient www.sciencedirect.com

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spreading [47]. FRAP and single molecule tracking experiments revealed that Septin7 at the neck of the spine slows down the diffusion of trans-membrane or inner leaflet-associated proteins between the spine and the dendrite shaft [44] (Figure 3c). In this context too, Septin functions are reminiscent of those in yeast. Septins (3, 5, 6, and 7) were also found distributed in presynaptic compartments [37,40,48–53]. Septin5 is found at the active zone (AZ) of immature giant synapses of the auditory brainstem, where it decreases synaptic output by preventing synaptic vesicle (SV) docking. In contrast at mature synapses, Septin5 is absent from the AZ and has no more effect on SV release [53] (Figure 3c). Despite their well-documented presence and the ability of Septins to bind proteins controlling SV release, their roles in the maturation and function of the presynaptic compartment remain largely unknown [10,48]. Thus, at the synapse, Septins emerge as key contributors in the acquisition of morphological specializations fundamental for neuronal functions.

Toward dynamic Septin codes in neurons Biochemical characterizations of Septin–Septin interactions and complexes in yeast and vertebrates uncovered important principles of their assembly and highlighted the variety of their oligomeric composition, arrangements and dynamics [2]. Now that several Septins’ functions have started to be assigned in neuronal development and physiology, the next step will be to identify specific contributions of individual Septins and different oligomers. First, Septin expression profiles suggest that different neurons express subsets of Septins, which vary according to their developmental stage [22,36,37,54]. For example, in the developing cerebral cortex, Septin4 and Septin14 expressions only start at mid-gestation in layers that contain intermediate neuronal progenitors and post-mitotic neurons [22]. In vitro, Septin6 was not detected in hippocampal neurons until they have specified their axons [40]. Septin genes can generate different isoforms, which thus rises additional diversity [42,54]. Spinal cord motoneurons undergo specific processing of Septin8 RNA, which results in a transcript containing an additional exon. This adds a motif known to promote the formation of filopodia and drives Septin8 protein palmitoylation. Interestingly, only the palmitoylated Septin8 isoform could rescue the dendrite arborization and spine formation defects induced by Septin8 loss [42]. Biochemical purification and immunolocalization experiments showed that co-expressed Septins do not necessarily oligomerize within the neurons. Septin14 associates with Septin4 and not with Septin3, 6, 7, or 11 in the developing cortex [22]. Similarly, only 24% of Septin6 was found associated with Septin7 in DRG neurons [34]. Consistently, different Septins could have obvious different subcellular distributions, [31,38], which might depend on isoform specificities as shown for Septin8 www.sciencedirect.com

[54] and on post-translational modification as shown for Septin7 in dendritic spines [47]. In agreement with a coexistence of different Septin structures in the neurons, functional differences were observed between different Septins. In the developing cortex, Septin3 loss of function does not phenocopy the migratory defects observed when Septin14 or 4 are depleted [22]. In cultured hippocampal neurons Septin7 that does not colocalize with Septin9 at the dendrite proximal segment, has no effect on KIF5 motor preference for axon transport [31]. Interestingly, even Septins that are present in the same compartment and that contribute to the same function could do so independently. Septins 6 and 7 are both recruited at branch points and promote collateral formation. However, Septin7 makes a chevron-like structure at the base of the nascent branch while Septin6 forms a punctum precisely where an actin patch forms. Functionally, Septin6 was shown to increase actin-patch formation while Septin7 which has no effect on this first step, contributes to facilitate microtubules unbundling and severing to promote their entry in the new branch [34] (Figure 3d). This illustrates that our vision of Septin complexes is oversimplified. For example, Septin7 might be dispensable in some contexts, and homooligomer form could be functional [31,55]. Combinations of different Septin complexes having different functional properties could enable specific morphological remodelling to occur simultaneously at distinct locations within a single neuron. Septin codes could also contribute to the diversity of neuronal morphologies.

Conclusion Yeasts are obviously not neurons and structuro-functional differences are progressively uncovered even among well-conserved proteins between yeast and vertebrates [56]. Yet, yeast is an inspiring model notably for polarity and recent works on yeast Septins will undoubtedly continue to fuel neurodevelopment researches. For example, Septin’s ability to supervise yeast shape as well as their conserved preference for positively curved membranes opens fascinating questions on their propensity to orchestrate the building of complex morphologies in neurons [57,58]. In yeast, post-translational modifications such as phosphorylation and sumoylation are crucial regulators of Septin dynamics, which has profound functional outcome [59]. How Septins switch from long-lasting structures to plastic state is another key question toward better understanding of their contributions to cell shapes and their transmission of over the generations.

Conflict of interest statement Nothing declared.

Acknowledgement This research was supported by ERC (European Research Council) grant 281604-YODA to V.C, conducted within the framework of the LABEX Current Opinion in Neurobiology 2019, 57:102–109

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CORTEX and Labex DevWeCAN of Universite´ de Lyon, within the program ‘Investissements d’Avenir’ (ANR-11-IDEX-0007) operated by the French National Research Agency (ANR).

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30. Ga¨rtner A, Fornasiero EF, Valtorta F, Dotti CG: Distinct temporal hierarchies in membrane and cytoskeleton dynamics precede the morphological polarization of developing neurons. J Cell Sci 2014, 127:4409-4419. 31. Karasmanis EP, Phan C-T, Angelis D, Kesisova IA,  Hoogenraad CC, McKenney RJ, Spiliotis ET: Polarity of neuronal membrane traffic requires sorting of kinesin motor cargo during entry into dendrites by a microtubule-associated septin. Dev Cell 2018, 46:204-218.e7. In this paper, the authors show how Septin9 controls sorting of membrane vesicles between axon and dendrites. In cultured hippocampal neurons, Septin9 progressively accumulate along microtubules at the base of the dendrites after their specification. Through recognition of motor proteins involved in polarized transport, Septin9 promotes transport of Kinesin3/ KIF1A dendritic cargoes into dendrites and impedes dendritic export of Kinesin1/KIF5 cargoes destined to axons. 32. Warenda AJ, Konopka JB: Septin function in Candida albicans morphogenesis. Mol Biol Cell 2002, 13:2732-2746. 33. Kelley JB, Dixit G, Sheetz JB, Venkatapurapu SP, Elston TC, Dohlman HG: RGS proteins and septins cooperate to promote chemotropism by regulating polar cap mobility. Curr Biol 2015, 25:275-285. 34. Hu J, Bai X, Bowen JR, Dolat L, Korobova F, Yu W, Baas PW, Svitkina T, Gallo G, Spiliotis ET: Septin-driven coordination of actin and microtubule remodeling regulates the collateral branching of axons. Curr Biol 2012, 22(12):1109-1115 Available at: http://linkinghub.elsevier.com/retrieve/pii/ S0960982212004113.. 35. Nozumi M, Togano T, Takahashi-Niki K, Lu J, Honda A, Taoka M, Shinkawa T, Koga H, Takeuchi K, Isobe T et al.: Identification of functional marker proteins in the mammalian growth cone. Proc Natl Acad Sci U S A 2009, 106:17211-17216. 36. Tada T, Simonetta A, Batterton M, Kinoshita M, Edbauer D, Sheng M: Role of septin cytoskeleton in spine morphogenesis and dendrite development in neurons. Curr Biol 2007, 17:1752-1758. 37. Tsang CW, Estey MP, DiCiccio JE, Xie H, Patterson D, Trimble WS: Characterization of presynaptic septin complexes in mammalian hippocampal neurons. Biol Chem 2011, 392 Available at: https://www.degruyter.com/view/j/bchm.2011.392. issue-8-9/bc.2011.077/bc.2011.077.xml.. 38. Xie Y, Vessey JP, Konecna A, Dahm R, Macchi P, Kiebler MA: The GTP-binding protein septin 7 is critical for dendrite branching and dendritic-spine morphology. Curr Biol 2007, 17:1746-1751. 39. Finger FP, Kopish KR, White JG: A role for septins in cellular and axonal migration in C. elegans. Dev Biol 2003, 261:220-234. 40. Cho S-J, Lee H, Dutta S, Song J, Walikonis R, Moon IS: Septin 6 regulates the cytoarchitecture of neurons through localization at dendritic branch points and bases of protrusions. Mol Cells 2011, 32:89-98. 41. Li X, Serwanski DR, Miralles CP, Nagata K, De Blas AL: Septin 11 is present in GABAergic synapses and plays a functional role in the cytoarchitecture of neurons and GABAergic synaptic connectivity. J Biol Chem 2009, 284:17253-17265. 42. Yuan Y, Xie S, Darnell JC, Darnell AJ, Saito Y, Phatnani H,  Murphy EA, Zhang C, Maniatis T, Darnell RB: Cell type-specific CLIP reveals that NOVA regulates cytoskeleton interactions in motoneurons. Genome Biol 2018, 19(1):117 Available at: http:// biorxiv.org/lookup/doi/10.1101/237347.. This study exemplifies how Septin isoforms could be selectively generated by cell-type specific RNA-regulations in the mouse spinal cord. In motoneurons, the neuron-specific RNA-binding proteins, NOVAs, which control alternative splicing and polyadenylation, promote exon10b inclusion in Septin8-RNAs.In vitro, the motoneuron-specific protein isoform, which contains a sequence known to induce filopodia and two palmityolation sites, is the only form rescuing dendritic arborization and spine formation after Septin8 knockdown. 43. Barral Y, Mansuy IM: Septins: cellular and functional barriers of neuronal activity. Curr Biol 2007, 17:R961-R963.

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44. Ewers H, Tada T, Petersen JD, Racz B, Sheng M, Choquet D: A septin-dependent diffusion barrier at dendritic spine necks. PLoS One 2014, 9:e113916. 45. Peng J, Kim MJ, Cheng D, Duong DM, Gygi SP, Sheng M: Semiquantitative proteomic analysis of rat forebrain postsynaptic density fractions by mass spectrometry. J Biol Chem 2004, 279:21003-21011. 46. Hall PA, Jung K, Hillan KJ, Russell SH: Expression profiling the human septin gene family. J Pathol 2005, 206:269-278. 47. Yadav S, Oses-Prieto JA, Peters CJ, Zhou J, Pleasure SJ,  Burlingame AL, Jan LY, Jan Y-N: TAOK2 kinase mediates PSD95 stability and dendritic spine maturation through Septin7 phosphorylation. Neuron 2017, 93:379-393. This article highlights the functional implication of post-translational modifications of Septins in neurons. Using Septin7 phosphomimetic and phosphomutants, the authors demonstrated that the TAOK2-dependent phosphorylation of Septin7 is required for dendritic spine formation. In cultured hippocampal neurons, phosphorylated Septin7 accumulates in spine heads where it exhibits reduced mobility. Phosphorylated Septin7 interacts with PSD95, which promotes PSD95 stabilization at the spine and could thereby facilitates spine maturation. 48. Beites CL, Xie H, Bowser R, Trimble WS: The septin CDCrel-1 binds syntaxin and inhibits exocytosis. Nat Neurosci 1999, 2:434-439. 49. Ihara M, Yamasaki N, Hagiwara A, Tanigaki A, Kitano A, Hikawa R, Tomimoto H, Noda M, Takanashi M, Mori H et al.: Sept4, a component of presynaptic scaffold and lewy bodies, is required for the suppression of a-synuclein neurotoxicity. Neuron 2007, 53:519-533. 50. Xue J, Milburn P, Hanna B, Graham M, Rostas J, Robinson P: Phosphorylation of septin 3 on Ser-91 by cGMP-dependent protein kinase-I in nerve terminals. Biochem J 2004, 381:753-760. 51. Xue J, Tsang CW, Gai W-P, Malladi CS, Trimble WS, Rostas JAP, Robinson PJ: Septin 3 (G-septin) is a developmentally regulated phosphoprotein enriched in presynaptic nerve terminals. J Neurochem 2004, 91:579-590. 52. Yoshida A, Yamamoto N, Kinoshita M, Hiroi N, Hiramoto T, Kang G, Trimble WS, Tanigaki K, Nakagawa T, Ito J: Localization of septin proteins in the mouse cochlea. Hear Res 2012, 289:40-51. 53. Yang Y-M, Fedchyshyn MJ, Grande G, Aitoubah J, Tsang CW, Xie H, Ackerley CA, Trimble WS, Wang L-Y: Septins regulate developmental switching from microdomain to nanodomain coupling of Ca2+ influx to neurotransmitter release at a central synapse. Neuron 2010, 67:100-115. 54. Ito H, Atsuzawa K, Morishita R, Usuda N, Sudo K, Iwamoto I, Mizutani K, Katoh-Semba R, Nozawa Y, Asano T et al.: Sept8 controls the binding of vesicle-associated membrane protein 2 to synaptophysin. J Neurochem 2009, 108:867-880. 55. Mendoza M, Hyman AA, Glotzer M: GTP binding induces filament assembly of a recombinant septin. Curr Biol 2002, 12:1858-1863. 56. Howes SC, Geyer EA, LaFrance B, Zhang R, Kellogg EH, Westermann S, Rice LM, Nogales E: Structural and functional differences between porcine brain and budding yeast microtubules. Cell Cycle 2018, 17:278-287. 57. Cannon KS, Woods BL, Gladfelter AS: The unsolved problem of how cells sense micron-scale curvature. Trends Biochem Sci 2017, 42:961-976. 58. Bridges AA, Jentzsch MS, Oakes PW, Occhipinti P, Gladfelter AS: Micron-scale plasma membrane curvature is recognized by the septin cytoskeleton. J Cell Biol 2016, 213:23-32. 59. Marquardt J, Chen X, Bi E: Architecture, remodeling, and functions of the septin cytoskeleton. Cytoskeleton 2018. Available at: http://doi.wiley.com/10.1002/cm.21475..

Current Opinion in Neurobiology 2019, 57:102–109