Dendritic Spine Formation Research Articles

Monocyte NLRP3-IL-1β Hyperactivation Mediates Neuronal and Synaptic Dysfunction in Perioperative Neurocognitive Disorder.

Perioperative neurocognitive disorder may develop in vulnerable patients following major operation. While neuroinflammation is linked to the cognitive effects of surgery, how surgery and immune signaling modulate neuronal circuits, leading to learning and memory impairment remains unknown. Using in vivo two‐photon microscopy, Ca2+ activity and postsynaptic dendritic spines of layer 5 pyramidal neurons in the primary motor cortex of a mouse model of thoracic surgery are imaged. It is found that surgery causes neuronal hypoactivity, impairments in learning‐dependent dendritic spine formation, and deficits in multiple learning tasks. These neuronal and synaptic alterations in the cortex are mediated by peripheral monocytes through the NLRP3 inflammasome‐dependent IL‐1β production. Depleting peripheral monocytes or inactivating NLRP3 inflammasomes before surgery reduces levels of IL‐1β and ameliorates neuronal and behavioral deficits in mice. Furthermore, adoptive transfer of IL‐1β‐producing myeloid cells from mice undertaking thoracic surgery is sufficient to induce neuronal and behavioral deficits in naïve mice. Together, these findings suggest that surgery leads to excessive NLRP3 activation in monocytes and elevated IL‐1β signaling, which in turn causes neuronal hypoactivity and perioperative neurocognitive disorder.

Loss of KCC2 in GABAergic Neurons Causes Seizures and an Imbalance of Cortical Interneurons.

K-Cl transporter KCC2 is an important regulator of neuronal development and neuronal function at maturity. Through its canonical transporter role, KCC2 maintains inhibitory responses mediated by γ-aminobutyric acid (GABA) type A receptors. During development, late onset of KCC2 transporter activity defines the period when depolarizing GABAergic signals promote a wealth of developmental processes. In addition to its transporter function, KCC2 directly interacts with a number of proteins to regulate dendritic spine formation, cell survival, synaptic plasticity, neuronal excitability, and other processes. Either overexpression or loss of KCC2 can lead to abnormal circuit formation, seizures, or even perinatal death. GABA has been reported to be especially important for driving migration and development of cortical interneurons (IN), and we hypothesized that properly timed onset of KCC2 expression is vital to this process. To test this hypothesis, we created a mouse with conditional knockout of KCC2 in Dlx5-lineage neurons (Dlx5 KCC2 cKO), which targets INs and other post-mitotic GABAergic neurons in the forebrain starting during embryonic development. While KCC2 was first expressed in the INs of layer 5 cortex, perinatal IN migrations and laminar localization appeared to be unaffected by the loss of KCC2. Nonetheless, the mice had early seizures, failure to thrive, and premature death in the second and third weeks of life. At this age, we found an underlying change in IN distribution, including an excess number of somatostatin neurons in layer 5 and a decrease in parvalbumin-expressing neurons in layer 2/3 and layer 6. Our research suggests that while KCC2 expression may not be entirely necessary for early IN migration, loss of KCC2 causes an imbalance in cortical interneuron subtypes, seizures, and early death. More work will be needed to define the specific cellular basis for these findings, including whether they are due to abnormal circuit formation versus the sequela of defective IN inhibition.

Insights Into the Emerging Role of Baf53b in Autism Spectrum Disorder.

Accurate and precise regulation of gene expression is necessary to ensure proper brain development and plasticity across the lifespan. As an ATP-dependent chromatin-remodeling complex, the BAF (Brg1 Associated Factor) complex can alter histone-DNA interactions, facilitating dynamic changes in gene expression by controlling DNA accessibility to the transcriptional machinery. Mutations in 12 of the potential 29 subunit genes that compose the BAF nucleosome remodeling complex have been identified in several developmental disorders including Autism spectrum disorders (ASD) and intellectual disability. A novel, neuronal version of BAF (nBAF) has emerged as promising candidate in the development of ASD as its expression is tied to neuron differentiation and it’s hypothesized to coordinate expression of synaptic genes across brain development. Recently, mutations in BAF53B, one of the neuron specific subunits of the nBAF complex, have been identified in patients with ASD and Developmental and epileptic encephalopathy-76 (DEE76), indicating BAF53B is essential for proper brain development. Recent work in cultured neurons derived from patients with BAF53B mutations suggests links between loss of nBAF function and neuronal dendritic spine formation. Deletion of one or both copies of mouse Baf53b disrupts dendritic spine development, alters actin dynamics and results in fewer synapses in vitro. In the mouse, heterozygous loss of Baf53b severely impacts synaptic plasticity and long-term memory that is reversible with reintroduction of Baf53b or manipulations of the synaptic plasticity machinery. Furthermore, surviving Baf53b-null mice display ASD-related behaviors, including social impairments and repetitive behaviors. This review summarizes the emerging evidence linking deleterious variants of BAF53B identified in human neurodevelopmental disorders to abnormal transcriptional regulation that produces aberrant synapse development and behavior.

Effects of ring finger and tryptophan-aspartic acid 2 on dendritic spines and synapse formation in cerebral cortex neurons of mice

To clarify the functional effects of differential expression of ring finger and tryptophan-aspartic acid 2 (RFWD2) on dendritic development and formation of dendritic spines in cerebral cortex neurons of mice. Immunofluorescent staining was used to identify the location and global expression profile of RFWD2 in mouse brain and determine the co-localization of RFWD2 with the synaptic proteins in the cortical neurons. We also examined the effects of RFWD2 over-expression (RFWD2-Myc) and RFWD2 knockdown (RFWD2-shRNA) on dendritic development, dendritic spine formation and synaptic function in cultured cortical neurons. RFWD2 is highly expressed in the cerebral cortex and hippocampus of mice, and its expression level was positively correlated with the development of cerebral cortex neurons and dendrites. RFWD2 expression was detected on the presynaptic membrane and postsynaptic membrane of the neurons, and its expression levels were positively correlated with the length, number of branches and complexity of the dendrites. In cultured cortical neurons, RFWD2 overexpression significantly lowered the expressions of the synaptic proteins synaptophysin (P < 0.01) and postsynapic density protein 95 (P < 0.01), while RFWD2 knockdown significantly increased their expressions (both P < 0.05). Compared with the control and RFWD2-overexpressing cells, the neurons with RFWD2 knockdown showed significantly reduced number of dendritic spines (both P < 0.05). RFWD2 can regulate the expression of the synaptic proteins, the development of the dendrites, the formation of the dendritic spines and synaptic function in mouse cerebral cortex neurons through ubiquitination of Pea3 family members and c-Jun, which may serve as potential treatment targets for neurological diseases.

Guanosine boosts the fast, but not sustained, antidepressant-like and pro-synaptogenic effects of ketamine by stimulating mTORC1-driven signaling pathway

The mTORC1-dependent dendritic spines formation represents a key mechanism for fast and long-lasting antidepressant responses, but it remains to be determined whether this mechanism may account for the ability of guanosine in potentiating ketamine's actions. Here, we investigated the ability of ketamine plus guanosine to elicit fast and sustained antidepressant-like and pro-synaptogenic effects in mice and the role of mTORC1 signaling in these responses. The combined administration of subthreshold doses of ketamine (0.1 mg/kg, i.p.) and guanosine (0.01 mg/kg, p.o.) caused a fast (1 h – 24 h), but not long-lasting (7 days) reduction in the immobility time in the tail suspension test. This behavioral effect was paralleled by a rapid (started in 1 h) and transient (back to baseline in 24 h) increase on BDNF, p-Akt (Ser473), p-GSK-3β (Ser9), p-mTORC1 (Ser2448), p-p70S6K (Thr389) immunocontent in the hippocampus, but not in the prefrontal cortex. Conversely, ketamine plus guanosine increased PSD-95 and GluA1 immunocontent in the prefrontal cortex, but not the hippocampus after 1 h, whereas increased levels of these proteins in both brain structures were observed after 24 h, but these effects did not persist after 7 days. The combined administration of ketamine plus guanosine raised the dendritic spines density in the ventral hippocampal DG and prefrontal cortex after 24 h Rapamycin (0.2 nmol/site, i.c.v.) abrogated the antidepressant-like effect and pro-synaptogenic responses triggered by ketamine plus guanosine. These results indicate that guanosine may boost the antidepressant-like effect of ketamine for up to 24 h by a mTORC1-dependent mechanism.

Tetraspanins as Potential Modulators of Glutamatergic Synaptic Function.

Tetraspanins (Tspans) comprise a membrane protein family structurally defined by four transmembrane domains and intracellular N and C termini that is found in almost all cell types and tissues of eukaryotes. Moreover, they are involved in a bewildering multitude of diverse biological processes such as cell adhesion, motility, protein trafficking, signaling, proliferation, and regulation of the immune system. Beside their physiological roles, they are linked to many pathophysiological phenomena, including tumor progression regulation, HIV-1 replication, diabetes, and hepatitis. Tetraspanins are involved in the formation of extensive protein networks, through interactions not only with themselves but also with numerous other specific proteins, including regulatory proteins in the central nervous system (CNS). Interestingly, recent studies showed that Tspan7 impacts dendritic spine formation, glutamatergic synaptic transmission and plasticity, and that Tspan6 is correlated with epilepsy and intellectual disability (formerly known as mental retardation), highlighting the importance of particular tetraspanins and their involvement in critical processes in the CNS. In this review, we summarize the current knowledge of tetraspanin functions in the brain, with a particular focus on their impact on glutamatergic neurotransmission. In addition, we compare available resolved structures of tetraspanin family members to those of auxiliary proteins of glutamate receptors that are known for their modulatory effects.

K+/Cl- co-transporter-2 upmodulation: a multi-modal therapy to treat spinal cord injury.

K+/Cl- co-transporter-2 upmodulation: a multi-modal therapy to treat spinal cord injury.

Sleep promotes the formation of dendritic filopodia and spines near learning-inactive existing spines

Changes in synaptic connections are believed to underlie long-term memory storage. Previous studies have suggested that sleep is important for synapse formation after learning, but how sleep is involved in the process of synapse formation remains unclear. To address this question, we used transcranial two-photon microscopy to investigate the effect of postlearning sleep on the location of newly formed dendritic filopodia and spines of layer 5 pyramidal neurons in the primary motor cortex of adolescent mice. We found that newly formed filopodia and spines were partially clustered with existing spines along individual dendritic segments 24 h after motor training. Notably, posttraining sleep was critical for promoting the formation of dendritic filopodia and spines clustered with existing spines within 8 h. A fraction of these filopodia was converted into new spines and contributed to clustered spine formation 24 h after motor training. This sleep-dependent spine formation via filopodia was different from retraining-induced new spine formation, which emerged from dendritic shafts without prior presence of filopodia. Furthermore, sleep-dependent new filopodia and spines tended to be formed away from existing spines that were active at the time of motor training. Taken together, these findings reveal a role of postlearning sleep in regulating the number and location of new synapses via promoting filopodial formation.

Planar cell polarity protein Vangl2 and its interacting protein Ap2m1 regulate dendritic branching in cortical neurons.

Van Gogh-like 2 (Vangl2) is a mammalian homolog of Drosophila core planar cell polarity (PCP) protein Vang/Strabismus, which organizes asymmetric cell axes for developmental proliferation, fate determination, and polarized movements in multiple tissues, including neurons. Although the PCP pathway has an essential role for dendrite and dendritic spine formation, the molecular mechanism remains to be clarified. To investigate the mechanism of Vangl2-related neuronal development, we screened for proteins that interact with the Vangl2 cytosolic N-terminus from postnatal day 9 mouse brains using a yeast two-hybrid system. From 61 genes, we identified adaptor-related protein complex 2, mu 1 subunit (Ap2m1) as the Vangl2 N-terminal binding protein. Intriguingly, however, the pull-down assay demonstrated that Vangl2 interacted with Ap2m1 not only at its N-terminus but also at the C-terminal Prickle binding domain. Furthermore, we verified that the downregulation of Ap2m1 in the developing cortical neurons reduced the dendritic branching similar to what occurs in a knockdown of Vangl2. From these results, we suggest that the membrane internalization regulated by the PCP pathway is required for the developmental morphological change in neurons.

Systematic expression analysis of plasticity-related genes in mouse brain development brings PRG4 into play.

Plasticity-related genes (Prgs/PRGs) or lipid phosphate phosphatase-related proteins (LPPRs) comprise five known members, which have been linked to neuronal differentiation processes, such as neurite outgrowth, axonal branching, or dendritic spine formation. PRGs are highly brain-specific and belong to the lipid phosphate phosphatases (LPPs) superfamily, which influence lipid metabolism by dephosphorylation of bioactive lipids. PRGs, however, do not possess enzymatic activity, but modify lipid metabolism in a way that is still under investigation. We analyzed mRNA expression levels of all Prgs during mouse brain development, in the hippocampus, neocortex, olfactory bulbs, and cerebellum. We found different spatio-temporal expression patterns for each of the Prgs, and identified a high expression of the uncharacterized Prg4 throughout brain development. Unlike its close family members PRG3 and PRG5, PRG4 did not induce filopodial outgrowth in non-neuronal cell lines, and does not localize to the plasma membrane of filopodia. We showed PRG4 to be highly expressed in the developing and the adult brain, suggesting that it is of vital importance for normal brain function. Despite its similarities to other family members, it seems not to be involved in changes of cell morphology; instead, it is more likely to be associated with intracellular signaling.

Hominini-specific regulation of CBLN2 increases prefrontal spinogenesis.

The similarities and differences between nervous systems of various species result from developmental constraints and specific adaptations1-4. Comparative analyses of the prefrontal cortex (PFC), a cerebral cortex region involved in higher-order cognition and complex social behaviours, have identified true and potential human-specific structural and molecular specializations4-8, such as an exaggerated PFC-enriched anterior-posterior dendritic spine density gradient5. These changes are probably mediated by divergence in spatiotemporal gene regulation9-17, which is particularly prominent in the midfetal human cortex15,18-20. Here we analysed human and macaque transcriptomic data15,20 and identified a transient PFC-enriched and laminar-specific upregulation of cerebellin 2 (CBLN2), a neurexin (NRXN) and glutamate receptor-δ GRID/GluD-associated synaptic organizer21-27, during midfetal development that coincided with the initiation of synaptogenesis. Moreover, we found that species differences in level of expression and laminar distribution of CBLN2 are, at least in part, due to Hominini-specific deletions containing SOX5-binding sites within a retinoic acid-responsive CBLN2 enhancer. In situ genetic humanization of the mouse Cbln2 enhancer drives increased and ectopic laminar Cbln2 expression and promotes PFC dendritic spine formation. These findings suggest a genetic and molecular basis for the anterior-posterior cortical gradient and disproportionate increase in the Hominini PFC of dendritic spines and a developmental mechanism thatmay link dysfunction of the NRXN-GRID-CBLN2 complex to the pathogenesis of neuropsychiatric disorders.

Abnormal dendritic morphology in the cerebellum of cyclooxygenase-2- knockin mice.

Prostaglandin E2 (PGE2) is a bioactive signalling molecule metabolized from the phospholipid membranes by the enzymatic activity of cycloxygenase-2 (COX-2). In the developing brain, COX-2 constitutively regulates the production of PGE2, which is important in neuronal development. However, abnormal COX-2/PGE2 signalling has been linked to neurodevelopmental disorders including autism spectrum disorders (ASDs). We have previously demonstrated that COX-2- -KI mice show autism-related behaviours including social deficits, repetitive behaviours and anxious behaviours. COX-2-deficient mice also have deficits in pathways involved in synaptic transmission and dendritic spine formation. In this study, we use a Golgi-COX staining method to examine sex-dependent differences in dendritic and dendritic spine morphology in neurons of COX-2- -KI mice cerebellum compared with wild-type (WT) matched controls at postnatal day 25 (P25). We show that COX-2- -KI mice have increased dendritic arborization closer to the cell soma and increased dendritic looping. We also observed a sex-dependent effect of the COX-2- -KI on dendritic thickness, dendritic spine density, dendritic spine morphology, and the expression of β-actin and the actin-binding protein spinophilin. Our findings show that changes in COX-2/PGE2 signalling lead to impaired morphology of dendrites and dendritic spines in a sex-dependant manner and may contribute the pathology of the cerebellum seen in individuals with ASD. This study provides further evidence that the COX-2- -KI mouse model can be used to study a subset of ASD pathologies.

Regulatory variants at 2q33.1 confer schizophrenia risk by modulating distal gene TYW5 expression.

Genome-wide association studies have shown that genetic variants at 2q33.1 are strongly associated with schizophrenia. However, potential causal variants in this locus and their roles in schizophrenia remain unknown. Here, we identified two functional variants (rs796364 and rs281759) that disrupt CTCF, RAD21 and FOXP2 binding at 2q33.1. We systematically investigated the regulatory mechanisms of these two variants with serial experiments, including reporter gene assays and electrophoretic mobility shift assay.Intriguingly, these two single nucleotide polymorphisms physically interacted with TYW5 and showed the most significant associations with TYW5 expression in human brain. Consistently, CRISPR-Cas9-mediated genome editing confirmed the regulatory effect of the two single nucleotide polymorphisms on TYW5 expression. Additionally, expression analysis indicated that TYW5 was significantly upregulated in brains of schizophrenia cases compared with controls, suggesting that rs796364 and rs281759 might confer schizophrenia risk by modulating TYW5 expression.We over-expressed TYW5 in mouse neural stem cells and rat primary neurons to mimic its upregulation in schizophrenia and found significant alterations in the proliferation and differentiation of neural stem cells, as well as dendritic spine density following TYW5 overexpression, indicating its important roles in neurodevelopment and spine morphogenesis.Furthermore, we independently confirmed the association between rs796364 and schizophrenia in a Chinese cohort of 8202 subjects. Finally, transcriptome analysis revealed that TYW5 affected schizophrenia-associated pathways. These lines of evidence consistently revealed that rs796364 and rs281759 might contribute to schizophrenia risk by regulating the expression of TYW5, a gene whose expression dysregulation affects two important schizophrenia pathophysiological processes (i.e. neurodevelopment and dendritic spine formation).

Novel ADNP Syndrome Mice Reveal Dramatic Sex-Specific Peripheral Gene Expression With Brain Synaptic and Tau Pathologies

BackgroundADNP is essential for embryonic development. As such, de novo ADNP mutations lead to an intractable autism/intellectual disability syndrome requiring investigation. MethodsMimicking humans, CRISPR (clustered regularly interspaced short palindromic repeats)–Cas9 editing produced mice carrying heterozygous Adnp p.Tyr718∗ (Tyr), a paralog of the most common ADNP syndrome mutation. Phenotypic rescue was validated by treatment with the microtubule/autophagy-protective ADNP fragment NAPVSIPQ (NAP). ResultsRNA sequencing of spleens, representing a peripheral biomarker source, revealed Tyr-specific sex differences (e.g., cell cycle), accentuated in females (with significant effects on antigen processing and cellular senescence) and corrected by NAP. Differentially expressed, NAP-correctable transcripts, including the autophagy and microbiome resilience–linked FOXO3, were also deregulated in human patient-derived ADNP-mutated lymphoblastoid cells. There were also Tyr sex-specific microbiota signatures. Phenotypically, Tyr mice, similar to patients with ADNP syndrome, exhibited delayed development coupled with sex-dependent gait defects. Speech acquisition delays paralleled sex-specific mouse syntax abnormalities. Anatomically, dendritic spine densities/morphologies were decreased with NAP amelioration. These findings were replicated in the Adnp+/− mouse, including Foxo3 deregulation, required for dendritic spine formation. Grooming duration and nociception threshold (autistic traits) were significantly affected only in males. Early-onset tauopathy was accentuated in males (hippocampus and visual cortex), mimicking humans, and was paralleled by impaired visual evoked potentials and correction by acute NAP treatment. ConclusionsTyr mice model ADNP syndrome pathology. The newly discovered ADNP/NAP target FOXO3 controls the autophagy initiator LC3 (microtubule-associated protein 1 light chain 3), with known ADNP binding to LC3 augmented by NAP, protecting against tauopathy. NAP amelioration attests to specificity, with potential for drug development targeting accessible biomarkers.

The autism risk gene CNTN4 modulates dendritic spine formation.

Contactin 4 (CNTN4) is a crucial synaptic adhesion protein that belongs to the contactin superfamily. Evidence from both human genetics and mouse models suggests that synapse formation and structural deficits strongly correlate with neurodevelopmental disorders, including autism. In addition, several lines of evidence suggest that CNTN4 is associated with the risk of autism. However, the biological functions of CNTN4 in neural development and disease pathogenesis are poorly understood. In this study, we investigated whether and how CNTN4 is autonomously involved in the development of dendrites and dendritic spines in cortical neurons. Disruption of Cntn4 decreased the number of excitatory synapses, which led to a reduction in neural activity. Truncated proteins lacking the signal peptide, FnIII domains or GPI domain lacked the ability to regulate dendritic spine formation, indicating that CNTN4 regulates dendritic spine density through a mechanism dependent on FnIII domains. Importantly, we revealed that autism-related variants lacked the ability to regulate spine density and neural activity. In conclusion, our study suggests that CNTN4 is essential for promoting dendrite growth and dendritic spine formation and that disruptive variants of CNTN4 interfere with abnormal synapse formation and may increase the risk of autism.

Structural connectivity and subcellular changes after antidepressant doses of ketamine and Ro 25-6981 in the rat: an MRI and immuno-labeling study

Ketamine has rapid and robust antidepressant effects. However, unwanted psychotomimetic effects limit its widespread use. Hence, several studies examined whether GluN2B-subunit selective NMDA antagonists would exhibit a better therapeutic profile. Although preclinical work has revealed some of the mechanisms of action of ketamine at cellular and molecular levels, the impact on brain circuitry is poorly understood. Several neuroimaging studies have examined the functional changes in the brain induced by acute administration of ketamine and Ro 25-6981 (a GluN2B-subunit selective antagonist), but the changes in the microstructure of gray and white matter have received less attention. Here, the effects of ketamine and Ro 25-6981 on gray and white matter integrity in male Sprague–Dawley rats were determined using diffusion-weighted magnetic resonance imaging (DWI). In addition, DWI-based structural brain networks were estimated and connectivity metrics were computed at the regional level. Immunohistochemical analyses were also performed to determine whether changes in myelin basic protein (MBP) and neurofilament heavy-chain protein (NF200) may underlie connectivity changes. In general, ketamine and Ro 25-6981 showed some opposite structural alterations, but both compounds coincided only in increasing the fractional anisotropy in infralimbic prefrontal cortex and dorsal raphe nucleus. These changes were associated with increments of NF200 in deep layers of the infralimbic cortex (together with increased MBP) and the dorsal raphe nucleus. Our results suggest that the synthesis of NF200 and MBP may contribute to the formation of new dendritic spines and myelination, respectively. We also suggest that the increase of fractional anisotropy of the infralimbic and dorsal raphe nucleus areas could represent a biomarker of a rapid antidepressant response.

The cranial windows of perception

Psilocybin has emerged as a potentially rapidly acting antidepressant with enduring actions. In this issue ofNeuron, Shao etal. (2021) show that psilocybin quickly induces dendritic spine formation in cortical layerV pyramidal neurons. These results provide a potential cellular substrate for psilocybin's therapeutic actions.

Neuron tracing and quantitative analyses of dendritic architecture reveal symmetrical three-way-junctions and phenotypes of git-1 in C. elegans.

Complex dendritic trees are a distinctive feature of neurons. Alterations to dendritic morphology are associated with developmental, behavioral and neurodegenerative changes. The highly-arborized PVD neuron of C. elegans serves as a model to study dendritic patterning; however, quantitative, objective and automated analyses of PVD morphology are missing. Here, we present a method for neuronal feature extraction, based on deep-learning and fitting algorithms. The extracted neuronal architecture is represented by a database of structural elements for abstracted analysis. We obtain excellent automatic tracing of PVD trees and uncover that dendritic junctions are unevenly distributed. Surprisingly, these junctions are three-way-symmetrical on average, while dendritic processes are arranged orthogonally. We quantify the effect of mutation in git-1, a regulator of dendritic spine formation, on PVD morphology and discover a localized reduction in junctions. Our findings shed new light on PVD architecture, demonstrating the effectiveness of our objective analyses of dendritic morphology and suggest molecular control mechanisms.

Neuronal VCP loss of function recapitulates FTLD-TDP pathology.

SUMMARYThe pathogenic mechanism by which dominant mutations in VCP cause multisystem proteinopathy (MSP), a rare neurodegenerative disease that presents as fronto-temporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), remains unclear. To explore this, we inactivate VCP in murine postnatal forebrain neurons (VCP conditional knockout [cKO]). VCP cKO mice have cortical brain atrophy, neuronal loss, autophago-lysosomal dysfunction, and TDP-43 inclusions resembling FTLD-TDP pathology. Conditional expression of a single disease-associated mutation, VCP-R155C, in a VCP null background similarly recapitulates features of VCP inactivation and FTLD-TDP, suggesting that this MSP mutation is hypomorphic. Comparison of transcriptomic and proteomic datasets from genetically defined patients with FTLD-TDP reveal that progranulin deficiency and VCP insufficiency result in similar profiles. These data identify a loss of VCP-dependent functions as a mediator of FTLD-TDP and reveal an unexpected biochemical similarity with progranulin deficiency.

WIP, YAP/TAZ and Actin Connections Orchestrate Development and Transformation in the Central Nervous System

YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif) are transcription co-regulators that make up the terminal components of the Hippo signaling pathway, which plays a role in organ size control and derived tissue homeostasis through regulation of the proliferation, differentiation and apoptosis of a wide variety of differentiated and stem cells. Hippo/YAP signaling contributes to normal development of the nervous system, as it participates in self-renewal of neural stem cells, proliferation of neural progenitor cells and differentiation, activation and myelination of glial cells. Not surprisingly, alterations in this pathway underlie the development of severe neurological diseases. In glioblastomas, YAP and TAZ levels directly correlate with the amount of the actin-binding molecule WIP (WASP interacting protein), which regulates stemness and invasiveness. In neurons, WIP modulates cytoskeleton dynamics through actin polymerization/depolymerization and acts as a negative regulator of neuritogenesis, dendrite branching and dendritic spine formation. Our working hypothesis is that WIP regulates the YAP/TAZ pools using a Hippo-independent pathway. Thus, in this review we will present some of the data that links WIP, YAP and TAZ, with a focus on their function in cells from the central and peripheral nervous systems. It is hoped that a better understanding of the mechanisms involved in brain and nervous development and the pathologies that arise due to their alteration will reveal novel therapeutic targets for neurologic diseases.