In conclusion, infusion of active caspase-3 to a level similar to that induced by NMDA treatment is sufficient to suppress synaptic transmission. We then performed similar experiments with recombinant BAD in its nonphosphorylated, active form. As shown in Figures 5A and Z-VAD-FMK clinical trial 5B, active caspase-3 was increased by 182 ± 18% at 1 hr of infusion (n = 5, p = 0.0001 for comparison of preinfusion and 1 hr of infusion), but when deactivated (boiled) BAD was used, active caspase-3 was increased only slightly (119 ± 7% of baseline at 1hr of infusion, n = 5, p = 0.058 for comparison of preinfusion and 1 hr of infusion). The cells infused with active BAD showed a run-down of EPSCs (76 ± 7% of baseline

at 1 hr of infusion, n = 9 slices from three mice, p = 0.013 for comparison of 2 min and 1 hr of infusion), while no such run-down was observed in cells infused with deactivated BAD or mutated BAD without the BH-3 domain through which BAD interacts with antiapoptotic BCL-2 family proteins (Youle and Strasser, 2008) (Figure 5D). The series resistance and input resistance were stable during the experimental period (Figures S4B and S4D), thus excluding cell death. Taken together, these data show that BAD and caspase-3 are sufficient to suppress synaptic currents. The above experiments established that BAD and BAX are required for caspase-3 activation and induction of LTD, but

not whether they act in a sequential or a parallel manner. To address this question, we check details performed similar infusion experiments as above with hippocampal slices prepared from mice deficient in either caspase-3, BAX or BAD. As shown in Figure 5D, Ribonucleotide reductase although infusion of active BAD suppressed synaptic currents in wild-type neurons, it did not alter them significantly in caspase-3 knockout cells (92 ± 8% of baseline at 1 hr of infusion, n = 9 slices from three mice, p = 0.42 for comparison of 2 min and 1 hr of infusion). Likewise, BAD infusion had no significant effect on the EPSCs of BAX knockout cells (91 ± 7% of baseline at 1 hr of infusion,

n = 9 slices from three mice, p = 0.31 for comparison of 2 min and 1 hr of infusion). Again, the series resistance and input resistance remained constant during these infusion experiments (Figure S4). These results indicate that BAD requires BAX and caspase-3 to suppress synaptic transmission. Furthermore, the impairment of synaptic depression in BAD knockout and BAX knockout cells can be rescued by infusing active caspase-3 (EPSCs at 1 hr of infusion with active caspase-3 in BAD knockout cells: 46 ± 6% of baseline, n = 9 slices from three mice, p = 0.0001 for comparison of 2 min and 1 hr of infusion; in BAX knockout cells: 52 ± 5% of baseline, n = 9 slices from three mice, p = 0.0001 for comparison of 2 min and 1 hr of infusion; Figure 5C).

In contrast, neither the Munc13-1W464R mutation nor the infusion of the CaM-inhibitory peptide in WT or Munc13-1W464R calyces had any deleterious effect on the recovery time course of the slowly releasing SV pool (Figure 3E). A reduced recovery rate of SV pools in Munc13-1W464R calyces was also evident when monitoring SV fusion by means of presynaptic membrane capacitance measurements, although the effect was less prominent, since this method reports the sum of fast and slow components (Figure S2). As elevations of presynaptic [Ca2+]i, e.g., upon changes in Ca2+ influx, strongly influence the recovery

of releasable SV pools (Dittman and Regehr, 1998; Sakaba and Neher, 2001; Stevens and Wesseling, 1998; Wang and Kaczmarek, 1998), we compared amplitudes of presynaptic NLG919 Ca2+ currents resulting from the depolarizing pulses between WT and Munc13-1W464R mutant calyces but found no significant differences (WT, 1238 ± 79 pA, n = 6; Munc13-1W464R, 1283 ± 56 pA, n = 6; p > 0.05). Likewise, no differences were observed in the recovery time course of presynaptic Erastin molecular weight Ca2+ currents, as the ratios between the Ca2+ current amplitudes triggered by the second versus the first depolarization stimulus were identical for all interstimulus intervals (Figure 3C). These data show that in young calyx synapses the W464R mutation in Munc13-1 selectively affects the recovery of the

fast releasing SV pool, much like CaM inhibitors do, indicating that the Ca2+-CaM effect on releasable SV pool refilling is mediated by Munc13-1. The lack of CaM binding to Munc13-1W464R in the KI mutant does not appear to affect presynaptic Ca2+

channels, which are known to bind CaM (DeMaria et al., 2001; Lee et al., 1999; Peterson et al., 1999; Zühlke et al., 1999). Calyx of Held synapses undergo a structural and functional mefexamide refinement during postnatal development that transforms these synapses into fast and reliable relays. These developmental modifications include changes in SV pools, release probability, postsynaptic receptor desensitization, and expression of Ca2+ binding proteins (Crins et al., 2011; Erazo-Fischer et al., 2007; Sonntag et al., 2011; Taschenberger et al., 2002; Taschenberger et al., 2005; Taschenberger and von Gersdorff, 2000; Wang et al., 2008). In light of these changes, we decided to study the recovery rates of the two SV pools and the dependency of the recovery rates on CaM in more mature WT and Munc13-1W464R calyces (P14–P17). We measured the recovery of the fast and slowly releasing SV pools following their depletion by a 50 ms depolarizing pulse in P14–P17 calyces under the same conditions as with P9–P11 calyces (see Figure 3). The cumulative release in WT calyces of P14–P17 animals exhibited two components (τ1 = 1.3 ± 0.5 ms, 60% of the total fit; τ2 = 11.

Analysis of GFP-expressing neurons at P18 revealed a significant increase in the number of dendritic spines on CA1 pyramidal neurons in NgRTKO−/− mice relative to their triple heterozygous littermate controls ( Figures 5A and 5B). These findings are

consistent with the idea that the NgR family members function together in vivo to limit the number of excitatory synapses. To extend this analysis using an independent approach, we performed transmission electron microscopy to visualize the ultrastructural features of excitatory synapses. In micrographs from NgRTKO−/− mice, we observed asymmetric synapses of typical morphology, suggesting that the overall structure and vesicle content of AZD6244 order excitatory synapses are normal in the absence of NgRs. However, quantification of the number of excitatory synapses in the apical dendritic regions of CA1 revealed that NgRTKO−/− mice had a significant

increase in the density of excitatory synapses relative to heterozygous littermate controls ( Figures 5C and 5D). Furthermore, this effect was not limited to CA1 neurons, since analysis of CA3 neurons also revealed a clear increase in the number of PSDs in NgRTKO−/− animals ( Figure 5E). Thus, analysis by confocal and electron microscopy suggests that the NgR family functions to limit the number of excitatory synapses in vivo. To address whether the observed increase in synapse number reflects an increase C59 concentration in functional synapses, we performed whole-cell patch-clamp electrophysiology on CA1 pyramidal neurons from acute hippocampal slices obtained from NgRTKO−/− mice and control littermates to quantify the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs). This analysis revealed a significant increase in the frequency of mEPSCs in

NgRTKO−/− mice relative to littermate controls ( Figure 5F and S5C), suggesting that the NgR family restricts the development of functional excitatory synapses. Interestingly, there was a small but significant from decrease in the amplitude of mEPSCs ( Figure 5G and S5D), consistent with the immature spine types observed in NgR1 knockouts ( Lee et al., 2008 and Zagrebelsky et al., 2010). Thus, reducing the expression of the NgR family results in an increase in functional synapses that are slightly reduced in strength. The question remained as to how NgRs work at a mechanistic level to restrict excitatory synapse number. One possibility was that NgRs limit the formation of new synapses in part by inhibiting dendritic growth, thereby reducing the possibility of contact between axons and dendrites. Therefore, we asked whether loss of NgR family members affects dendritic branching.

This is consistent with the two trials (Kjellman and Oberg

2002, Viljanen et al 2003) that reported medium- (WMD –2, 95% CI –7 to 4) and long-term (WMD –0.1, 95% CI –6 to 6) pain outcomes. Pooled results from the two trials that reported disability outcomes (Kjellman and Oberg 2002, Viljanen et al 2003) from general strength and conditioning exercise showed no significant difference compared with minimal intervention at the conclusion of treatment (WMD 1, 95% CI –3 to 5) or medium- (WMD 1, 95% CI –3 to 5) or long-term (WMD –3, 95% PI3K Inhibitor Library cell line CI –7 to 2) follow-up. Manual therapy: In the three included trials of manipulation, there were four sham-controlled comparisons of the immediate analgesic effect of a single high-velocity manipulation. One trial ( Cleland et al 2005) investigated the effect of thoracic spine manipulation on neck pain and two trials ( Martinez-Segura et al 2006, Pikula 1999) investigated cervical spine manipulation. The three-arm trial by Pikula

and colleagues (1999) compared two different manipulation techniques with sham. The two manipulation groups in this trial were combined to create a single pair-wise comparison. Three trials SAR405838 molecular weight ( Hemmila 2005, Hoving et al 2002, 2006, Skillgate et al 2007) were identified that compared manual therapy with minimal or no intervention. Pooled outcomes from three trials (Cleland et al 2005, Martinez-Segura et al 2006, Pikula 1999) show a significant analgesic benefit from a single manipulation compared with control (WMD –22, 95% CI –32 to –11). Medium- and longterm outcomes were not reported in these trials. Disability was not assessed. Pooled outcomes from two trials (Hoving et al 2002, Skillgate

et al 2007) show that manual therapy provided better pain relief after a course of treatment than minimal treatment (WMD –12, 95% CI –16 to –7). A Modulators similar benefit was not reported in the single trial (Hoving et al 2006) that reported medium- (MD –7, 95% CI –16 to 2) and long-term (MD –1, 95% CI –11 to 9) pain outcomes. Pooled outcomes from three trials (Hemmila 2005, Hoving et al 2002, Skillgate et al 2007) show that manual therapy resulted in significantly better disability TCL outcomes at the conclusion of treatment than control (WMD –6, 95% CI –11 to –2). A similar benefit was not demonstrated in the two trials (Hemmila 2005, Hoving et al 2006) that reported medium- (WMD –8, 95% CI –24 to 7) and long-term (WMD –1, 95% CI –12 to 9) disability outcomes. Multimodal physical therapies: Two trials compared multimodal physical therapies, which included exercises, massage, and various electrotherapies, with minimal treatment. One trial excluded manual therapies ( Hoving et al 2002, 2006), and one trial included manual therapies ( Palmgren et al 2006) in the range of treatments provided.

The WHO vaccine position papers, available in English, French, Arabic, Chinese, Russian

and Spanish, summarize the recommendations of SAGE and serve as key reference documents. [6] Comments from vaccine manufacturers to the position papers are sought through e-consultations, while aware of potential conflicts of interest and equity. SAGE has also provided guidance to vaccination in humanitarian emergencies, based on assessment of the epidemiological risk, vaccine characteristics, and prioritization in the context of other urgent public health needs and security, financial, and Libraries political realities. New SAGE working groups will be formed to review evidence leading to updating recommendations on the use of Japanese SRT1720 clinical trial encephalitis,

pertussis, varicella, hepatitis E, and malaria vaccines among others. N. Dellepiane gave updated information on WHO Prequalification (PQ) procedures, focusing on the strategic priorities, including securing the supply base for priority vaccines for developing countries, facilitating access to quality products, improving efficiency of the prequalification procedure and to expanding portfolio for vaccine introduction. Related activities were conducted including the amendment of several WHO guidance documents [7], [8], [9], [10], [11], [12], [13], [14] and [15], the implementation of expedited/facilitated registration procedure for prequalified vaccines in receiving countries, BMS-754807 cost and two WHO workshops in China and India targeting at manufacturers with potential for PQ of priority vaccines. In 2013, L-NAME HCl an Internet based tool has been developed and hosted on WHO-server

for online submission, processing and monitoring of registration applications. She introduced the features of the revised procedure, notably, the Programmatic Suitability of Product Characteristics (PSPQ) committee, the streamlined prequalification procedure of 6 months for manufacturers in countries with eligible authorities, and the establishment of annual reporting systems (PQVARs). Finally, a customers’ survey was made of PQ service design (PQ process) and service delivery. Still, there are concerns about overall time required for prequalification and process time inefficiencies (e.g. overall elapsed time, knowing when to expect a response). Manufacturers would like to see samples tested in parallel to the review of the file, while this may not be feasible to implement. In addition, there is a need for harmonization of expectations between different GMP auditors, categorization of deviations and of GMP code applied. This year the first open Chief Executive Officers (CEOs) Panel Discussion held at an annual general meeting was moderated by H. Dabas, from the Clinton Health Access Initiative (CHAI). CEOs from 9 DCVMN member companies discussed how to turning challenges into opportunities. A.

Des modulations de ce profil de base peuvent être apportées par l’influence contraire de l’IMC sur le taux plasmatique de SHBG [71] ou par l’apparition d’une neuropathie qui peut participer à la constitution d’un déficit testiculaire primaire [72]. L’ensemble des données de la littérature suggère donc que, par des mécanismes complexes, le déficit en androgènes soit un des facteurs favorisant l’émergence

d’un diabète ou l’aggravation d’un diabète préexistant. Ainsi que cela est désormais recommandé par l’American Modulators Diabetes Association (ADA) selleck screening library ceci incite à rechercher l’existence d’un hypogonadisme chez le patient dont le diabète est connu. Il convient également de détecter l’émergence d’un diabète ou l’aggravation d’un diabète préexistant chez le patient dont la pathologie relève d’un traitement par blocage androgénique. Les conséquences des modifications métaboliques associées à l’hypogonadisme ne sont pas négligeables. S’inscrit au premier rang le risque vasculaire. Une importante étude de cohorte chez des septuagénaires a montré, après ajustement pour les autres principaux facteurs confondants, que le risque de survenue d’un accident vasculaire cérébral ou

d’un accident ischémique transitoire était deux fois plus élevé lorsque le taux de testostérone plasmatique total ou libre était bas [73]. Le phénotype métabolique retrouvé chez l’homme hypogonadique pourrait ainsi constituer le lien physiopathologique entre hypotestostéronémie et complications vasculaires et possiblement risque vital. Laughlin et al. ont mis en évidence dans une check details cohorte d’hommes âgés suivis sur une période de dix ans que le risque de décès était presque doublé chez ceux

dont le taux de testostérone plasmatique à l’entrée dans l’étude était le plus bas [74]. Il faut remarquer que dans cette étude les causes cardiovasculaires de décès sont le plus fréquemment observées sans pouvoir bien sûr conclure qu’il y ait un lien direct entre testostéronémie et risque vital. Les résultats des évaluations transversales et longitudinales issues de la Framingham Heart Study, et recueillies chez plusieurs milliers d’hommes suivis all au long terme, montrent que l’association entre testostéronémie libre et SMet disparaît après ajustement pour l’âge, l’IMC et la sensibilité à l’insuline. Les liens identifiés entre testostérone totale, d’une part, SMet et risque vasculaire, d’autre part, s’expliquent en fait par la corrélation linéaire qui existe entre testostéronémie totale et taux plasmatique de SHBG [75]. Les taux de testostérone plasmatique totale sont étroitement liés à ceux de la SHBG. Le taux plasmatique de la protéine de transport apparaît être un facteur indépendant associé au risque de survenue d’un SMet [76]. Ce dernier, modulé par l’âge, l’IMC et le degré d’insulino-résistance, apparaît donc comme un marqueur plus fiable de ce risque.

Results of analysis of clinical materials suggest that the quantity of residual hcDNA is approximately 0.1 ng/dose. In addition, the DNA size analysis we conduct indicate that the median size of residual DNA is 450 bp with 64% of

the hcDNA less than 500 bp in length and no detectable DNA above 1000 bp. Substituting E[U] = 1, and Med0 = 1000 in Eq. (18) and Eq. (19), the safety factors of oncogenicity and infectivity are estimated to be 4.9 × 1010 and 2.2 × 1011, ROCK signaling pathway which represent worst case scenario of safety factor estimates. In general, using the analytical methods discussed in Section 3.5, variability associated with the estimate of the median size Med0 of residual DNA can be obtained. For example, we could perform the analysis on a large number of samples, to give rise to a set of estimates of median size. The error related to the mean median size of residual DNA can be calculated. Applying Taylor expansion, the error associated with safety factor estimate can be determined. Alternatively, we could use bootstrapping method to estimate the error, based on resampling of samples from the size distribution MK-1775 concentration determined by the method in [13]. This will allow us to construct one-sided confidence lower bound for the safety factor, which represents

the worst case scenario. Lastly, the theoretical model is developed in a very general context. It can easily be applied to the inhibitors evaluation of oncogenic and infective risks of other biological products. The assessment of the intranasal vaccine serves as an illustration to the use of the method. As we have demonstrated, the use of the method is simple and straightforward. For interested parties a written computer code of the method can be obtained by contacting the first author. We thank the

referees for their valuable comments that have helped to improve the manuscript greatly. “
“Type next 1 diabetes mellitus is an autoimmune process in which T cells invade the pancreatic islet and lead to inappropriate inflammation [1]. The inflammation selectively causes the functional inactivation and ultimately the death of the insulin-producing β cells [2]. Many important factors in the pathogenesis of the autoimmune process have been understood. Inflammation and autoimmunity to autoantigens are part of the progression of the disease [3]. Nevertheless, the fact that type 1 diabetes results from an autoimmune disease tells us that β cell destruction can be stopped by arresting the inflammatory autoimmune process. Several autoantigens identified as targets for diabetogenic T cells in the autoimmune diabetes [3], an Hsp60 peptide contained between aa 437 and 460 named P277 is one of them [4]. The important factor impeding the development of P277 vaccine is its poor immunogenicity.

To determine the extent and duration of suppression of mutant huntingtin synthesis achievable with ASO infusion into the nervous system, a 20-mer phosphorothioate modified oligonucleotide complementary to human huntingtin mRNA (HuASO) and containing 2′-O-(-2-methoxy) ethyl modifications on the five nucleotides on the 3′ and 5′ ends to increase its stability, tolerability and potency (Bennett and

Swayze, 2010, Henry et al., 2001 and Yu et al., 2004) was infused continuously (10, 25, or 50 μg/day) for 2 weeks into the right lateral ventricle of the BACHD mouse model of HD. BACHD mice harbor a full-length mutant human SB431542 manufacturer huntingtin gene with an expansion of 97 CAG/CAA repeats and express the mutant protein at approximately 1.5 times the level of the endogenous mouse huntingtin (Gray

et al., 2008). Infusion of the HuASO significantly decreased the levels of human huntingtin mRNA in a dose-dependent manner (Figure 1A) (25 μg/day, to 42% of the level of vehicle alone [p = 0.007]; 50 μg/day, to 28% vehicle [p = 0.005]). For all subsequent studies a dose of 50 μg/day of HuASO was used. At the end of infusion, the ASO had accumulated to significant levels (170 ± 16 μg/g brain tissue) that then decreased GS 1101 in abundance with approximately first order kinetics over a subsequent 16 week period (Figure 1B). This pharmacokinetic profile is similar to that observed in peripheral tissues following systemic administration of similarly modified ASOs (Yu et al., 2001). At all times postinfusion, more than 90% of the remaining ASO was full length, as judged by capillary gel electrophoresis, indicating the ASO was chemically stable within cells of the nervous system. A significant reduction in human huntingtin mRNA levels (reduced to 38% ± 3% [p < 0.001] Electron transport chain of the vehicle-infused animals) was observed at the earliest time point (after 2 weeks of continuous infusion). This

reduction persisted for 12 weeks, rising back to untreated levels only 16 weeks after the termination of treatment (Figure 1C). At 12 weeks posttreatment, only 13 μg/g of ASO was present in the brain (Figure 1B), yet huntingtin reduction persisted, indicating that low doses of ASO in the correct cellular compartments are sufficient to be effective and are maintained with long in vivo half lives, particularly in the brain where many of the cells are nondividing. A similar pattern of reduction was observed for the accumulated mutant human huntingtin protein; however, the reduction was delayed relative to the mRNA (Figure 1D), reflecting a longer half-life of the protein than the mRNA. Nevertheless, by 4 weeks posttermination of ASO infusion, mutant human huntingtin protein levels were reduced by two-thirds and gradually returned to untreated levels 16 weeks after the end of infusion (Figure 1D).

Indeed, this idea is supported by genetic studies of bHLH and homeodomain transcription factors in ventral neural tube that regulate glial subtype identity (Molofsky et al., 2012) and show segmental origins of astrocytes. We fate mapped astrocyte origins throughout the brain and spinal cord using cre recombinase expressed in multiple region-restricted progenitor click here domains (Tsai et al., 2012). What we observed was surprisingly simple. Astrocytes in all domains migrated laterally along radial glial trajectories and never exhibited secondary migration from their domains of origin. Even adult astrocytes

challenged by injury or depletion of astrocytes in particular domains by diphtheria toxin A (DTA) failed to provoke secondary emigration. Thus, the final location of astrocytes can predict their regional origins, raising the possibility that they become diversified for local functions in CNS. This “segmental model” for astrocyte allocation is illustrated in Figure 4. In addition to allocation, recent work has shown that the “Segmental

selleck screening library Model” holds true for understanding supracellular domain organization of astrocytes into functional units in cortex (Magavi et al., 2012), heterogeneity of type B stem cells of the SVZ (Merkle et al., 2007), and localized proliferation of intermediate astrocyte precursors (Tien et al., 2012). Future work might prove the existence of

“astromeres” by showing specific astrocyte-encoded functions that play precise regional roles tailored to the particular locations that they occupy (Figure 4). The term astromere is meant to capture the immutable pattern Adenosine of astrocyte segmental allocation, and the speculative notion that this could result in an astrocyte scaffold that retains positional information encoded during patterning. For instance, motor neurons of ventral spinal cord interact with multiple cell types as part of the sensory motor circuit responsible for most basic involuntary and voluntary movements. Their axons traverse long distances to reach targets in the periphery and they receive indirect inputs of long-range signaling from upper neurons in the brain. Astroglia in the locale of motor neurons might therefore have undergone intense selective pressure to optimally support their neuron neighbor. Indeed, a recent study showed that the initial trajectory of type 1a sensory axons was unaffected in FoxP1 mouse mutants with mislocalized MN targets ( Sürmeli et al., 2011), suggesting the possibility that nonneuronal cells—perhaps astrocytes—encode the critical region-restricted guidance cues. We envisage that astromeres could function as local domains to direct axon guidance, as well as regional features involved in synapse formation/pruning, levels of neuronal activity, and even neuronal subtype survival.

Similar to results in mass cultures, NGF treatment of distal axons leads to a reduction (24% decrease) in phosphorylated dynamin1, in comparison to control treatment (Figure 5C and 5D). To test whether NGF regulates phosphorylation of dynamin1 in axons in vivo, we analyzed the levels of phospho-dynamin1 in a sympathetic target tissue, the salivary glands, in both wild-type and heterozygous NGF (NGF+/−) mice. Given that dynamin1 is neuron specific ( Urrutia et al., 1997), immunoblotting of salivary gland lysates with the phospho-dynamin1 antibody should reveal the status of dynamin1 phosphorylation Bleomycin locally in sympathetic nerve terminals that innervate

the target tissue. If target-derived NGF regulates dynamin1 phosphorylation

in vivo, then we would expect to see increased dynamin1 phosphorylation levels under conditions of reduced NGF signaling. We employed NGF+/− mice for this analysis because these mice display haploinsufficiency with reduced levels of NGF and sympathetic target innervation ( Brennan et al., 1999 and Ghasemlou et al., 2004), in contrast to homozygous selleck compound NGF null mice, which completely lack sympathetic innervation ( Glebova and Ginty, 2004). We found that NGF+/− mice have higher levels of phosphorylated dynamin1 on Ser-778 in sympathetic axons innervating the salivary glands, compared to wild-type animals (11.2% ± 2% increase;

Figures 5E and 5F). These findings provide in vivo evidence for NGF-dependent phosphoregulation of dynamin1 locally in sympathetic axons. To assess the role of dynamin1 dephosphorylation in supporting neurotrophin-dependent axon growth, sympathetic neurons were exposed for 24 hr to a cell-permeable peptide spanning the dynamin1 phospho-box (amino acids 769–784, incorporating Ser-774 and Ser-778) in which the two serines 774/778 were replaced with alanine (Ser774/778-Ala, dyn1769-784AA). The dyn1769-784AA peptide blocks dephosphosphorylation-dependent dynamin1 functions by binding and sequestering downstream effector molecules, such as syndapin1 (Anggono et al., 2006). Delivery of dyn1769-784AA (300 μM) into sympathetic neurons reduced NGF-mediated axon growth from an Cell press average of 177 ± 14 μm/day to 90.6 ± 7.2 μm/day (Figures 5G, 5H, and 5M). In contrast, introduction of the phospho-mimetic peptide dyn1769-784EE (in which the serines 774/778 were substituted with glutamate) had no effect on NGF-mediated axon growth (Figures 5I and 5M). NT-3-mediated axon growth was not affected by delivery of either dyn1769-784AA or dyn1769-784EE (Figures 5J, 5K, 5L, and 5M). Together, these results provide evidence that calcineurin-mediated dephosphorylation of dynamin1 is a key signaling mechanism necessary for NGF-mediated, but not NT-3-mediated, axon growth.