Disruptions in this balance contribute to neurodevelopmental abnormalities that selleckchem can affect the gross size and organization of the nervous system (Pang et al., 2008) or impair cognitive and motor functions (Courchesne et al., 2007). An important step toward understanding the basis of these defects thus lies in defining the gene regulatory pathways that regulate NPC renewal. Throughout development, NPCs are organized in a polarized neuroepithelial sheet that surrounds the ventricles, termed the ventricular zone (VZ). This arrangement fosters progenitor-progenitor contacts that serve as a self-supporting

neural stem cell niche (Zhang et al., 2010). Within this compartment, NPCs exhibit a characteristic bipolar radial morphology mediated by two points of adhesion. At their apical pole, NPCs adhere

to the luminal surface of the ventricle through N-cadherin-based adherens junctions (AJs) formed between neighboring NPCs, while their basal end-feet are attached to the subpial extracellular matrix through integrin-laminin interactions (Meng and Takeichi, 2009). AJs maintain the radial morphology and self-renewal of NPCs by anchoring a variety of signaling proteins to the actin cytoskeleton. Some of the best studied of these factors include the following: (1) members of the catenin/armadillo protein family (α, δ, γ, and β-catenin, the latter of which also mediates the proliferative activity of the Wnt signaling pathway) (Farkas and Huttner, 2008, Meng and Takeichi, 2009 and Stepniak this website et al., 2009); (2) Par proteins, aPKC, and Cdc42, which control apical-basal polarity (Cappello et al., 2006, Manabe et al., 2002 and Sottocornola et al., 2010); and (3) Numb, an asymmetrically distributed regulator of Notch pathway activity and neuronal differentiation (Cayouette and Raff, 2002 and Rasin et al., 2007). Most studies of AJs in NPCs have focused

on how these signaling complexes are assembled to sustain Ribonucleotide reductase the neuroepithelial state. However, a less understood, but equally important aspect is the means by which AJs are disassembled to permit NPC differentiation and migration away from the VZ. This process must be tightly regulated, as blocking the expression or activity of AJ components causes NPCs to delaminate, resulting in widespread disruption of the neuroepithelium and deformation of the neural tube (Cappello et al., 2006, Chen et al., 2006, Ghosh et al., 2008, Imai et al., 2006, Kadowaki et al., 2007, Rasin et al., 2007, Zechner et al., 2003 and Zhang et al., 2010). To study this critical step in neurogenesis, we have focused on the formation of motor neurons (MNs) in the spinal cord. MN progenitors are specified at an early stage in development through the convergent actions of Sonic hedgehog and retinoic acid signaling, which direct a network of transcription factors centered around the bHLH protein Olig2 to promote MN differentiation (Briscoe and Novitch, 2008).

Chambers were positioned over FEF/PFC (one chamber with access to both regions) and SEF using stereotaxic coordinates (FEF/PFC: A25, L20; SEF: A25, midline). In the same surgery, IOX1 we implanted scleral search coils. Animals recovered for 1–2 weeks before training resumed. Procedures were approved by and conducted under the auspices of the University of Pittsburgh Institutional Animal

Care and Use Committee and were in compliance with the guidelines set forth in the United States Public Health Service Guide for the Care and Use of Laboratory Animals. To determine appropriate target locations for the metacognition task (described below), we initially characterized the receptive field of each neuron using simple visual oculomotor tasks (see Sommer and Wurtz, 2004). First, the monkey made visually guided saccades to targets in eight directions (cardinal directions and diagonals). After the neuron’s preferred direction was established, the monkey performed visually guided saccades

of varying amplitudes in that direction. If necessary, directions and amplitudes were adjusted, and the tasks were repeated to refine the assessment of the field. Once the receptive field center was located, we had the monkey make memory-guided saccades to that location, to distinguish visual-, delay-, and saccade-related activity (Mays and Sparks, 1980). We accepted neurons with any combination of these signals. The task was described previously in detail (Middlebrooks and

Sommer, 2011). Each trial consisted of a Decision 4-Aminobutyrate aminotransferase Stage and a Bet Stage, separated by an interstage period (Figure 1A). In the decision selleckchem stage the animal was required to detect and report the location of a masked visual target (Thompson and Schall, 1999), and in the bet stage was required to report, via a wager, whether a correct or incorrect decision had been made in the decision stage (Shields et al., 2005). Appropriate betting, thus optimal reward delivery, required the animal to maintain a representation of its decision. It is the maintenance of that decision signal, and its use for betting, that we refer to as metacognition. To obtain reward on any trial, completion of both the decision and bet stages was required. Decision Stage. The monkey fixated a spot for 500–800 ms (randomized; Figure 1A, left). Then, a dim target appeared in one of four possible locations (also randomized). The locations were constant in a session but could vary between sessions; eccentricities ranged from 5–25 degrees and directions, relative to horizontal, ranged from 0–60 degrees. For each neuron, these parameters were chosen so that, when possible, at least one target location was in the receptive field center. The locations were mirror symmetric across the vertical meridian. After the target appeared, identical mask stimuli (white squares) appeared at all four locations.

These localizations agree well with ultra high-resolution light microscopy studies that place RIM closer

to the plasma membrane than piccolo and bassoon (Dani et al., 2010). Interestingly, ultra-high resolution light microscopy has also been used in Drosophila to reconstruct at least part of an active zone with the t-bar that is characteristic for Drosophila active zones ( Figure 4B; Liu et al., 2011). EM tomography in C. elegans synapses also revealed dense projections to which synaptic vesicles are attached ( Stigloher et al., 2011). Gratifyingly, mutations in RIM or α-liprin disrupted the Antiinfection Compound Library in vitro attachment of synaptic vesicles in C. elegans active zones, consistent with the functional assignments of these proteins described above. Together, these results support the notion http://www.selleckchem.com/products/hydroxychloroquine-sulfate.html that the core complex

of active zone proteins is involved in linking synaptic vesicles, Ca2+ channels, and the fusion machinery to each other at the plasma membrane ( Figure 3). In cryo-EM studies of unfixed and unstained synapse preparations, however, no dense projections are detectable. The only structures visible are the plasma membrane, synaptic vesicles, and sparse filaments that either connect vesicles to each others (“connectors,” average length ∼10 nm) or tether vesicles to the presynaptic plasma membrane (“tethers”—5–20 nm; Landis et al., 1988 and Fernández-Busnadiego et al., 2010). No other structures are visible, even though the cytosol clearly must contain abundant protein complexes as described above. Is the view of the active zone obtained with fixed Resveratrol or with unfixed materials correct? It has been argued that EM with unfixed preparations is superior to EM on chemically fixed preparations because chemical fixatives, by their very nature,

crosslink proteins, and thus may create structures that are not normally present (Siksou et al., 2009; Fernández-Busnadiego et al., 2010). However, high-pressure freezing of samples is not devoid of potential problems since it generally involves a long preincubation in hyperosmotic medium, is not instantaneous, and subjects a sample to very high pressures. Clearly the fact that in cryo-EM images the protein complexes that are known to mediate the functions of the active zone are invisible does not mean these complexes are not there. Nevertheless, the dense projections observed in chemically fixed preparations would have been seen in cryo-EM images given their size, suggesting that these projections represent the result of chemical fixation. A plausible hypothesis thus is that chemical cross-linking of the active zone core protein complexes generates these dense projections.

5 (Figures 1A and 1B). At E9.5, Pou3f4 expression in the presumptive mesenchyme is not detectable (Figure 1A); however, at E10.5, small patches of Pou3f4-expressing mesenchyme cells emerge adjacent to the cvg buy Luminespib (Figure 1B, see arrows). By E12.5, when the auditory and vestibular components of the inner ear have diverged (Koundakjian et al., 2007), Pou3f4 is detectable in all compartments of the otic mesenchyme (Figure 1C).

At this stage, neural crest-derived Schwann cells infiltrate the ganglia, and SGNs begin to project peripheral axons toward the prosensory domain located within the cochlear epithelium (Carney and Silver, 1983). At these early stages, Pou3f4 is detectable in otic mesenchyme cells, but not in neurons, glia, or epithelia. Moreover, Pou3f4-expressing mesenchyme cells appear to make direct contact with the distal ends of the SGN peripheral axons (Figure 1C,

arrowheads) in regions where Schwann cells have not yet arrived. At E16.5, SGN peripheral axon outgrowth continues along the length of the cochlea as the otic mesenchyme (om) population expands to form the future osseous spiral lamina and spiral limbus (osl and sl, respectively; Figures 1D and 1E). The adult osl consists of bony plates that surround the SGN axons, and the sl is a thickened periosteum. At E15.5–E16.5, radial bundles form concurrently with the appearance of bands of mesenchyme cells located between SGN peripheral axons (as in Figure 2G, asterisks). By P2, Pou3f4-positive mesenchyme selleck compound PDK4 cells segregate from extending SGN axons, with clearly visible boundaries (Figure 1E). Occasional Pou3f4-positive cells were observed within the somal layer of the spiral ganglion (Figure 1E), but these cells were not

positive for either Tuj1 or Sox10, suggesting that they are mesenchyme cells that have interspersed the ganglion during development (arrows in Figures 1E and 1F). In whole mount at E17.5, the segregation of the peripheral axons and the otic mesenchyme is dramatic: groups of ∼50–100 axons fasciculate to form relatively evenly spaced inner radial bundles along the length of the cochlea (Figures 1G–1I). Higher-magnification images show how axons travel in areas that are devoid of Pou3f4 and rarely cross between bundles (Figures 1J–1O). Previously, Pou3f4 mutants were shown to have variable levels of hypoplasia of the otic mesenchyme and severe hearing impairment ( Minowa et al., 1999 and Phippard et al., 1999). Therefore, we hypothesized that if SGN fasciculation and otic mesenchyme organization are interdependent, then inner radial bundle formation may require Pou3f4. To test this hypothesis, we compared radial bundle development in whole-mount preparations of Pou3f4y/+ and Pou3f4y/− cochleae ( Figures 2A–2H). At E17.5, Pou3f4y/+ cochleae contained dense, well-organized fascicles that projected directly from the SGN soma to the cochlear epithelium ( Figures 2A–2C).

The first clear defect was a decrease in N-cadherin staining starting around 12 hr posttransfection,

followed thereafter by a loss of Sox2 staining and cytoplasmic accumulation of Numb at 24 hr posttransfection, and the ectopic formation of NeuN+ neurons within the VZ by 36 hr posttransfection (Figures 4A–4O). We did not observe any notable elevation of either Ngn2 or NeuroM above that already present in the spinal cord during this time course (data not shown), suggesting that the prodifferentiation actions of Foxp4 work downstream or in parallel with endogenous proneural gene activity. We next FACS-isolated transfected cells from the electroporated spinal cords and measured mRNA expression levels using quantitative selleck screening library PCR. Foxp4 misexpression resulted in an ∼45% decrease in N-cadherin mRNA within 6 hr and

an ∼65% decrease by 12 hr postelectroporation ( Figure 4P). We did not observe any significant decrease in the expression of other AJ genes such as β-catenin, Obeticholic Acid in vitro Cdc42, RhoA, and aPKCζ at the 6 hr time point, though β-catenin mRNA was moderately reduced by 12 hr postelectroporation ( Figure 4P). Despite this latent β-catenin reduction, we did not detect any changes in β-catenin activity as measured by a cotransfected Wnt/β-catenin-responsive reporter, TOP-dGFP ( Dorsky et al., 2002), or find any correlation between reporter expression and the endogenous pattern of Foxp4 expression ( Figures S2S–S2V). These results suggest that the decline in β-catenin levels may be secondary to N-cadherin loss. In evaluating the expression of other genes, we found that Foxp4 potently suppressed Sox2 mRNA by ∼70% within 6 hr postelectroporation Dipeptidyl peptidase ( Figure 4P). Despite this early transcriptional effect, Sox2 protein did not decline until ∼18–24 hr postelectroporation, at which time N-cadherin was undetectable ( Figures 4A, 4B, 4F, and 4G). Together, these data indicate that Foxp4 can rapidly suppress both N-cadherin and Sox2 mRNA expression, but N-cadherin protein is more labile such that it declines

before Sox2 and thus initiates the process of neuroepithelial detachment. To confirm that Foxp4 directly regulates N-cadherin, we aligned the genomic sequence of the chick, mouse, and human Cdh2 (N-cadherin) loci and identified several evolutionarily conserved regions within introns 2 and 3 that contained canonical Foxp binding sites ( Figures 4Q and S6A–S6G). Foxp4 binding to these elements was measured through chromatin immunoprecipitation assays using differentiating MN progenitors produced in vitro from mouse embryonic stem cells as a proxy for spinal cord tissue. Foxp4 binding was prominent at a highly conserved element within intron 3 [i3a] but not at other sites tested ( Figures 4Q and S6).

This project was supported by CNPq, FAPESP (No. 2007/56082-4) (Brazil)

and INIA-FPTA No. 243 (Uruguay). “
“The Publisher regrets that an error occurred in Table 2 of the original article. The full corrected Table 2 appears below: “
“Figure options Download full-size image Download as PowerPoint slide 2010 will always be remembered as the year we lost our friend and colleague Peter Van Den Bossche in a tragic car accident. Peter was universally recognized for his research in the field of tsetse flies and trypanosomiasis. His interest for this subject dated back to 1985 when after obtaining his degree of doctor in veterinary medicine at Ghent University, Belgium, he applied to the Institute of Tropical Medicine (ITM) for volunteer work. During this training the first breeding colony of tsetse flies at ITM was set up. It was a very rudimentary, BKM120 but successful experiment carried out in the cellars of the institute. Peter’s desire to proceed with this research pushed him into registering for a training course at ITM, where he obtained in 1987 the diploma of tropical veterinary medicine and animal husbandry. His thesis work was on the development of a permanent breeding colony of tsetse flies at ITM. This breeding colony still exists and has since become an invaluable instrument in various ITM research programmes. After a few additional years of research work at ITM Peter left the

institute selleckchem and choose to carry out fieldwork in Africa. He was active in several projects that controlled animal trypanosomiasis and its vector, first in Zambia and later in the whole South African Region. Due to his field and research experience, Peter acquired an international reputation as an expert in the control of vector-transmitted parasites and in the understanding of their epidemiology. With his lucid vision, his pragmatic approach and his exciting

enthusiasm, he undertook many field studies in collaboration with colleagues from before the North as well as from the South. Southern Africa became his second home. Moreover, beside his appointment as professor at ITM, Peter was also an extraordinary professor at the University of Pretoria. At his job Peter distinguished himself through his enormous zest for work and his enthusiasm, which he succeeded in transferring to the many students he supervised. Because of his investigatory spirit, his helpfulness and his friendly attitude, Peter always knew to motivate and inspire his students and collaborators. His pleasant character and eternal optimism meant that he had many friends among his colleagues within as well as outside ITM. Peter has always been an early bird who started the days’ work whistling and whose clear and positive vision was a guiding inspiration for his scientific collaborators. His multiple projects and missions abroad did not prevent him from enjoying life.

, 2003; Ljungberg et al., 1992; Matsumoto and Hikosaka, 2009), exhibit a phasic prediction error (PE) response signaling the difference between outcome and expectation (Bromberg-Martin et al., 2010; Schultz et al., 1997). Moreover, PE signals originating in ventral midbrain neurons are relayed through a widespread network of connections (Lidow et al., 1991; Lindvall et al., 1974), resulting in increased dopamine

release (Gonon, 1988; Zhang et al., 2009), activity modulation (Pessiglione et al., 2006), and plasticity (Surmeier et al., 2010) at projection sites. Accordingly, a recent human fMRI study has shown that reward information was present throughout most brain regions tested (Vickery et al., 2011). Therefore, the highly selective behavioral and neural effects induced by stimulus-reward pairings must be TGF-beta inhibitor reconciled with the apparent widespread and diffuse nature of neuromodulatory reward signals.

A potential explanation for this seeming contradiction is that selectivity arises through an interaction between a broadly distributed reward signal and coincident bottom-up, cue-driven activity. In this way, a diffuse dopaminergic reward signal is rendered selective, allowing reward to specifically modulate BKM120 in vivo activity within reward-predicting cue representations (Roelfsema et al., 2010; Seitz and Watanabe, 2005). In agreement with this interpretation, the pairing of an auditory stimulus with microstimulation of the ventral tegmental area (VTA), Mannose-binding protein-associated serine protease a surrogate for reward, specifically enhanced the representation of a stimulation-paired frequency within rat auditory cortex in a dopamine-dependent manner (Bao et al., 2001). In addition, Pleger et al. (2009) has found a stimulus-selective, dopaminergic

reward feedback signal within human somatosensory cortex. Surprisingly though, direct evidence for selective reward modulations in primate visual cortex has not yet been demonstrated. This is probably due to the difficulty of disentangling reward from other co-occurring cognitive factors such as attention (Maunsell, 2004). For example, while Serences (2008) found that the association of a visual stimulus with a higher reward probability resulted in stimulus-selective increases in fMRI activity, the contributions of reward and attention to these results are indistinguishable. Weil et al., (2010) also looked at the effects of direct stimulus-reward relationships in visual cortex. In an effort to isolate reward effects from attention, they temporally disassociated reward from stimulus presentation. This study, however, found only a main effect of reward outside the representation of the visual stimulus suggesting these reward modulations were stimulus aspecific. In order to differentiate the contributions of attention and reward, we developed a paradigm for investigating cue-selective reward modulations that were temporally separated from discrete cue-reward association trials.

Of the nonspiking neurons, 61% (11/18) exhibited membrane potential oscillations in phase with ventral root bursts ( Figures 5C and 5F). Thus, Shox2 INs are rhythmically active during drug-evoked locomotor-like activity. We next analyzed, separately, the set of Shox2 INs located in predominantly flexor-related (L2 and L3) or extensor-related (L4 and L5) segments.

We found that EGFR phosphorylation 20/27 of the Shox2 INs in L2/L3 spiked rhythmically whereas only 12/25 of the L4/L5 Shox2 INs spiked rhythmically. For both rhythmic firing and membrane oscillations, there was a clear flexor dominance. We found that 70% of neurons in L2/L3 (14/20) spiked in phase with local flexor-related ventral root activity, whereas in L4/L5, spiking was equally divided into flexor- and extensor-related neurons. Approximately 60% of L2/L3 (15/26) and of L4/L5 (13/21) Shox2 INs had the depolarizing peak in the flexor phase. Therefore, regardless of segment, most Shox2 INs are rhythmically active in the flexor-phase. This finding is in contrast to rhythmic Chx10-GFP neurons (a mix of Shox2+ and Shox2off V2a neurons), where flexor- and extensor-related neurons were evenly distributed throughout the lumbar cord (Dougherty and Kiehn, 2010a and Dougherty and Kiehn, 2010b). Our electrophysiological findings on Shox2 INs reveal preferential activation

of Shox2 INs during the flexor phase of locomotion. To determine whether this feature is correlated with connectivity profiles detected at the premotor level, we evaluated connectivity between Shox2 INs and motor neurons. First, we injected a floxed-synaptophysin-GFP adeno-associated http://www.selleckchem.com/products/birinapant-tl32711.html virus into the spinal cords of P3 Shox2::Cre mice and monitored the presence of GFP-labeled Shox2 IN terminals on motor neurons at P17 ( Figures 6A–6D). We observed many Shox2 IN terminals in lamina IX, often in apposition to motor neuron somata and proximal dendrites ( Figures 6A–6C). Shox2 IN terminals

were also detected in the intermediate zone Phosphatidylinositol diacylglycerol-lyase and in lamina VIII, the settling position of other CPG interneurons. High-resolution reconstructions of synaptic input from Shox2 INs to motor neurons innervating ankle flexor tibialis anterior (TA) or ankle extensor gastrocnemius (GS) muscles, specifically marked by retrograde labeling from the muscle, revealed a Shox2 IN synaptic bias toward flexor (TA) motor neurons ( Figure 6D). To determine the position of Shox2 INs that are monosynaptically connected to motor neurons, we performed retrograde transsynaptic labeling by the application of rabies viruses with monosynaptic restriction (Stepien et al., 2010 and Tripodi et al., 2011). We carried out unilateral virus injections coincidently into several hindlimb muscles to target many premotor neurons. We found that ∼50% of Shox2 INs in the rostral lumbar spinal cord were transsynaptically marked from hindlimb innervating motor neurons, whereas this fraction decreases caudally (Figures 6E–6G).

We observed map plasticity in every group that we mapped within 20 days of the beginning of training or NBS low-tone pairing. However, we did not observe map plasticity in any of the groups that were mapped >35 days after the beginning of training or NBS low-tone pairing. These results confirm that map plasticity Doxorubicin in vitro is a transient phenomenon that occurs during the first few weeks of discrimination training. In naive rats with no behavior training or NBS-tone pairing,

the representation of low and high tones is approximately equal (Figure 4A, black square). We quantified map plasticity by measuring the ratio of the A1 surface area responding to a 2 kHz tone and a 19 kHz tone at 60 dB SPL (Figures

4A and S1). To confirm that training alone was sufficient to generate map plasticity, a Behavior Alone group (n = 6 rats, 311 A1 sites) was trained to perform the low-frequency discrimination task, but had no NBS-tone pairing (Figure 4B). As expected, these rats exhibited significant low-frequency map plasticity. Fifty percent more neurons responded to low-frequency tones compared to high-frequency tones (Figure 4A, Naive versus Behavior Alone, p = 0.019, t test). This result confirms that 20 days of behavior training generated a low-frequency map expansion. The pretraining procedure for the Pretrained Groups in Experiment 2 was identical to the procedure for the Behavior Alone group, and so all three Pretrained Groups selleck inhibitor must also have had low-frequency map expansions after 20 days of behavior almost training (Figures 4B and 4C). Twenty days of additional NBS-tone pairing followed by

10 days of additional behavior testing led to map renormalization in the Pretrained groups so that the organization of these rat’s auditory cortex was similar to naive animals (circles in Figure 4A; p > 0.15 for all groups, Figure S1). Renormalization occurred in all three groups, even though two groups experienced NBS-tone pairing and the control group experienced no NBS. All three Pretrained groups experienced the same behavior testing during the 10 days before physiology, implying that this 10 day period was sufficient to renormalize map plasticity in all three groups. Behavioral performance for all three Pretrained groups was not different from the Behavior Alone group immediately before physiology [Figures 4B and 4C; F(3,21) = 0.6664, p = 0.8369]. The observation that the Pretrained rats with map renormalization discriminated tones as well as rats with map plasticity (Behavior Alone) indicates that map plasticity is not necessary to accurately perform the low-frequency discrimination task. These results are consistent with previous reports that map plasticity occurs during learning and that map renormalization occurs even when training continues (Ma et al., 2010, Molina-Luna et al., 2008, Takahashi et al.

Similarly, AC proteins, capping protein, and Arp2/3 are sufficient to recapitulate Listeria motility in vitro (Loisel et al., 1999). How do AC proteins

help to drive actin retrograde flow and organization? And how does this influence neurite formation (Figures 8F and 8G)? The location of actin polymerization is tightly regulated, occurring nearly exclusively at the leading edge of growth cones (Forscher and Smith, 1988), probably due to the linkage of actin nucleators to the membrane (Pak et al., 2008; Saarikangas et al., 2010). As they grow, actin filaments (Figure 8F, red) undergo molecular aging, so that the original ATP-actin (light red subunits) becomes ADP-actin (dark red subunits) over time and at locations distant from the www.selleckchem.com/products/MK-2206.html membrane. Since AC proteins (yellow spheres) bind preferentially to this older, ADP-actin portion of filaments, actin depolymerization, severing (Pac-Man), turnover and reorganization, is promoted away from the leading edge. Indeed, we found that active AC is positioned at the base of filopodia and lamellipodia, ideally poised for dismantling F-actin. In the absence of AC proteins, Epigenetics Compound Library nmr attenuated actin disassembly

may lead to the congestion of the intracellular space with actin filaments that reorient haphazardly in response to the pressure of polymerization. Hence, AC may regulate actin organization simply by virtue of its primary activity: increasing actin turnover. Consistent with this view, the reintroduction of Cofilin function restored retrograde flow and reorganized actin superstructures. Our data further show that actin retrograde flow is driven by Cofilin’s propensity for F-actin severing.

These data are consistent with current actin turnover modeling, which indicates that the most effective way to achieve accelerated actin retrograde flow would be to enhance actin deconstruction at the minus end of filaments (Roland et al., crotamiton 2008). Filopodia have recently been linked to neuritogenesis as they engorge with microtubules and elongate into nascent neurites (Dent et al., 2007). From this work and our own results, it is plausible that these radial actin bundles are the sites where microtubules can extend into the peripheral zone in the correct, radial orientation, which is necessary for the consolidation and advance of a nascent neurite (Figure 8F). AC knockout neurons displayed a marked decrease in radially oriented actin filaments in lamellipodia and filopodia while concomitantly exhibiting abnormal microtubule growth patterns and looping trajectories. Thus, the lack of this permissive actin platform for microtubules to grow along may underlie the failure of neuritogenesis in AC KO neurons. However, neuritogenesis is also attenuated in situations where filopodia appear normal, such as in ADF monoallele neurons and wild-type neurons treated with low levels of jasplakinolide. Thus, actin dynamics is also important for this process.