KCND2 variants associated with global developmental delay differentially impair Kv4.2 channel gating.

Here, we report on six unrelated individuals, all presenting with early-onset global developmental delay, associated with impaired motor, speech and cognitive development, partly with developmental epileptic encephalopathy and physical dysmorphisms. All individuals carry heterozygous missense variants of KCND2, which encodes the voltage-gated potassium (Kv) channel α-subunit Kv4.2. The amino acid substitutions associated with the variants, p.(Glu323Lys) (E323K), p.(Pro403Ala) (P403A), p.(Val404Leu) (V404L) and p.(Val404Met) (V404M), affect sites known to be critical for channel gating. To unravel their likely pathogenicity, recombinant mutant channels were studied in the absence and presence of auxiliary ß-subunits under two-electrode voltage clamp in Xenopus oocytes. All channel mutants exhibited slowed and incomplete macroscopic inactivation, and the P403A variant in addition slowed activation. Co-expression of KChIP2 or DPP6 augmented the functional expression of both wild-type and mutant channels; however, the auxiliary ß-subunit-mediated gating modifications differed from wild type and among mutants. To simulate the putative setting in the affected individuals, heteromeric Kv4.2 channels (wild type + mutant) were studied as ternary complexes (containing both KChIP2 and DPP6). In the heteromeric ternary configuration, the E323K variant exhibited only marginal functional alterations compared to homomeric wild-type ternary, compatible with mild loss-of-function. By contrast, the P403A, V404L and V404M variants displayed strong gating impairment in the heteromeric ternary configuration, compatible with loss-of-function or gain-of-function. Our results support the etiological involvement of Kv4.2 channel gating impairment in early-onset monogenic global developmental delay. In addition, they suggest that gain-of-function mechanisms associated with a substitution of V404 increase epileptic seizure susceptibility.

Impact of dental restorations and removable prostheses on potentially malignant oral mucosal disorders in the general population.

STATEMENT OF PROBLEM: Dental restorations and removable dental prostheses have been considered as risk factors for potentially malignant disorders of the oral mucosa. It remains unclear whether amalgam, composite resins, and prosthesis materials can induce potentially malignant disorders. PURPOSE: The purpose of this clinical study was to determine the relationship between the presence of amalgam and composite resin restorations, crowns and fixed partial dentures, and removable prostheses in potentially malignant disorders. MATERIAL AND METHODS: The data of 6041 participants in the population-based Studies of Health in Pomerania (SHIP) were accessed. Potentially malignant disorders had been clinically diagnosed by calibrated dentists and documented with photographs. Dental treatment was subdivided into restored and replaced teeth. Dental restorations were subclassified as buccal composite resin or amalgam restorations. Prosthetic treatment was subclassified into removable partial or complete prostheses and definitive restorations with crowns and fixed partial dentures. RESULTS: In the maxilla, participants with removable prostheses had a higher incidence of potentially malignant disorders than participants not undergoing treatment with removable prostheses (OR 2.12; 95% CI: 1.08-4.18), but not in the mandible (OR 1.30; 95% CI: 0.67-2.53). The surfaces with composite resin restorations were associated with a slightly higher risk of mucosal lesions than those without the restorations (OR 1.04; 95% CI: 1.01-1.07). No significant association was found between amalgam restorations and mucosal lesions. CONCLUSIONS: Participants with removable prostheses have a higher risk of potentially malignant disorders. Composite resin restorations are associated with a higher risk of mucosal lesions, whereas no significant association was found between amalgam restorations and mucosal lesions.

Dominant KPNA3 Mutations Cause Infantile-Onset Hereditary Spastic Paraplegia.

OBJECTIVE: Hereditary spastic paraplegia (HSP) is a highly heterogeneous neurologic disorder characterized by lower-extremity spasticity. Here, we set out to determine the genetic basis of an autosomal dominant, pure, and infantile-onset form of HSP in a cohort of 8 patients with a uniform clinical presentation. METHODS: Trio whole-exome sequencing was used in 5 index patients with infantile-onset pure HSP to determine the genetic cause of disease. The functional impact of identified genetic variants was verified using bioinformatics and complementary cellular and biochemical assays. RESULTS: Distinct heterozygous KPNA3 missense variants were found to segregate with the clinical phenotype in 8 patients; in 4 of them KPNA3 variants had occurred de novo. Mutant karyopherin-α3 proteins exhibited a variable pattern of altered expression level, subcellular distribution, and protein interaction. INTERPRETATION: Our genetic findings implicate heterozygous variants in KPNA3 as a novel cause for autosomal dominant, early-onset, and pure HSP. Mutant karyopherin-α3 proteins display varying deficits in molecular and cellular functions, thus, for the first time, implicating dysfunctional nucleocytoplasmic shuttling as a novel pathomechanism causing HSP. ANN NEUROL 2021;90:738-750.

Prevalence of SARS-CoV-2 IgG antibodies among dental teams in Germany.

OBJECTIVES: During the corona pandemic, dental practices temporarily closed their doors to patients except for emergency treatments. Due to the daily occupational exposure, the risk of SARS-CoV-2 transmission among dentists and their team is presumed to be higher than that in the general population. This study examined this issue among dental teams across Germany. MATERIALS AND METHODS: In total, 2784 participants provided usable questionnaires and dry blood samples. Dry blood samples were used to detect IgG antibodies against SARS-CoV-2. The questionnaires were analyzed to investigate demographic data and working conditions during the pandemic. Multivariable logistic mixed-effects models were applied. RESULTS: We observed 146 participants with positive SARS-CoV-2 IgG antibodies (5.2%) and 30 subjects with a borderline finding (1.1%). Seventy-four out of the 146 participants with SARS-CoV-2 IgG antibodies did not report a positive SARS-CoV-2 PCR test (50.7%), while 27 participants without SARS-CoV-2 IgG antibodies reported a positive SARS-CoV-2 PCR test (1.1%). Combining the laboratory and self-reported information, the number of participants with a SARS-CoV-2 infection was 179 (6.5%). Though after adjustment for region, mixed-effects models indicated associations of use of rubber dams (OR 1.65; 95% CI: 1.01-2.72) and the number of protective measures (OR 1.16; 95% CI: 1.01-1.34) with increased risk for positive SARS-CoV-2 status, none of those variables was significantly associated with a SARS-CoV-2 status in fully adjusted models. CONCLUSIONS: The risk of SARS-CoV-2 transmission was not higher among the dental team compared to the general population. CLINICAL RELEVANCE: Following hygienic regulations and infection control measures ensures the safety of the dental team and their patients.

Effects of cold physical plasma on oral lichen planus: An in vitro study (Effects of CAP on OLP).

OBJECTIVES: In the search for more effective and safe treatment avenues, we investigated cold physical plasma as a new treatment modality for therapy of oral lichen planus (OLP). MATERIAL AND METHODS: Healthy and diseased human mucosal tissue samples with a size of 3 mm in diameter obtained from OLP patients were subjected to plasma treatment ex vivo or were left untreated. Tissue sections were quantified for immune-infiltration of CD4+ , CD8+ , CD45RA+ , and CD45R0+ T cells. Moreover, the tissues' inflammatory profile was assessed by analyzing 12 different cytokines in the surrounding media. RESULTS: A significantly increased infiltrate of CD8+ and CD45-R0+ T cells was detected in OLP tissue samples when compared to healthy tissue. A higher concentration of interleukin (IL) 1ß, IL6, IL8, and granulocyte macrophage-colony stimulating factor (GM-CMF) was detected in OLP samples compared to healthy mucosal tissue. For all cytokines and chemokines investigated, 23 out of 24 comparisons showed a decrease in tendency (significant for IL1ß, IL2, IL10, and GM-CSF) in response to plasma treatment. In ex vivo-treated tissue, a decrease of T-cell infiltrate in OLP lesions compared with healthy tissue was observed. CONCLUSION: Our findings suggest cold physical plasma can be a promising therapeutic option for OLP that requires further validation in vivo.

De Novo Missense Mutations in DHX30 Impair Global Translation and Cause a Neurodevelopmental Disorder.

DHX30 is a member of the family of DExH-box helicases, which use ATP hydrolysis to unwind RNA secondary structures. Here we identified six different de novo missense mutations in DHX30 in twelve unrelated individuals affected by global developmental delay (GDD), intellectual disability (ID), severe speech impairment and gait abnormalities. While four mutations are recurrent, two are unique with one affecting the codon of one recurrent mutation. All amino acid changes are located within highly conserved helicase motifs and were found to either impair ATPase activity or RNA recognition in different in vitro assays. Moreover, protein variants exhibit an increased propensity to trigger stress granule (SG) formation resulting in global translation inhibition. Thus, our findings highlight the prominent role of translation control in development and function of the central nervous system and also provide molecular insight into how DHX30 dysfunction might cause a neurodevelopmental disorder.

New insights in the link between malocclusion and periodontal disease.

AIM: We aimed to investigate associations between malocclusions and periodontal disease by comparing it to that of smoking in subjects recruited from the population-based cross-sectional study "Study of Health in Pomerania." MATERIALS AND METHODS: Sagittal intermaxillary relationship, variables of malocclusion and socio-demographic parameters of 1,202 dentate subjects, 20-39 years of age, were selected. Probing depth (PD) and attachment loss (AL) were assessed at four sites by tooth in a half-mouth design. Analyses were performed with multilevel models on subject, jaw and tooth level. RESULTS: Distal occlusion determined in the canine region, ectopic position of canines, anterior spacing, deep anterior overbite and increased sagittal overjet were associated with AL (p-value <0.05). Associations between malocclusions and PD: deep anterior overbite with gingival contact (odds ratio [OR] = 1.40, 95% CI: 1.08-1.82; p-value = 0.0101) and anterior crossbite (OR = 1.75, 95% CI: 1.29-2.38; p-value = 0.0003). Regarding crowding, only severe anterior crowding was compatible with a moderate to large association with PD (OR = 1.93, 95% CI: 0.89-4.20). Compared to smoking, the overall effect of malocclusions was about one half for AL and one-third for PD. CONCLUSION: Malocclusions or morphologic parameters were associated with periodontal disease.

Do Third Molars Contribute to Systemic Inflammation? Results From a Population-Based Study From Northeast Germany.

PURPOSE: Erupted and impacted third molars have been reported to contribute to systemic inflammation. This study investigated the systemic effect of third molars on serum levels of inflammatory parameters and on inflammatory messenger peptide hormones in a general population sample. MATERIALS AND METHODS: Data of 2,151 participants from the Study of Health in Pomerania were included in this study. Erupted or impacted third molars were assessed with whole-body magnetic resonance imaging at 1.5 T and associated with biomarkers of inflammation, lipid metabolism, glucose metabolism, and peptide hormones by linear regression. Models were adjusted for age, gender, smoking status, education, and type 2 diabetes mellitus. RESULTS: Neither erupted nor impacted third molars were associated with high-sensitivity C-reactive protein, white blood cell count, or fibrinogen as markers for systemic inflammation. Participants with erupted third molars had markedly lower serum levels of leptin (ß coefficient, -2.47; 95% confidence interval [CI], -4.47 to -0.48), angiopoietin-2 (ß coefficient, -135.1; 95% CI, 248.6 to -21.5), and ratio of angiopoietin-2 to tyrosine kinase with immunoglobulin-like loop epidermal growth factor homology domain 2 (ß coefficient, -6.57; 95% CI, -13.06 to -00.7) than participants without third molars. No such associations were observed for impacted third molars. CONCLUSION: The present results did not substantiate a relation between third molars and an increase in systemic inflammatory markers. Therefore, dental practitioners should be careful when considering this as the only indication for removal of third molars, especially in medically compromised patients. The results of this study showed that participants with erupted third molars had lower levels of messenger peptide hormones, such as leptin and angiopoetin-2.

Alexithymia and temporomandibular joint and facial pain in the general population.

BACKGROUND: Associations of alexithymia with temporomandibular pain disorders (TMD), facial pain, head pain and migraine have been described, but the role of the different dimensions of alexithymia in pain development remained incompletely understood. OBJECTIVES: We sought to investigate the associations of alexithymia and its subfactors with signs of TMD and with facial pain, head pain and migraine in the general population. METHODS: A total of 1494 subjects from the general population completed the Toronto Alexithymia Scale-20 (TAS-20) and underwent a clinical functional examination with palpation of the temporomandibular joint and masticatory muscles. Facial pain, migraine and head pain were defined by questionnaire. A set of logistic regression analyses was applied with adjustment for age, sex, education, number of traumatic events, depressive symptoms and anxiety. RESULTS: Alexithymia was associated with TMD joint pain (Odds Ratio 2.63; 95% confidence interval 1.60-4.32 for 61 TAS-20 points vs the median of the TAS-20 score) and with facial pain severity (Odds Ratio 3.22; 95% confidence interval 1.79-5.79). Differential effects of the subfactors were discovered with difficulties in identifying feelings as main predictor for joint, facial, and head pain, and externally oriented thinking (EOT) as U-shaped and strongest predictor for migraine. CONCLUSION: Alexithymia was moderately to strongly associated with signs and symptoms of TMD. These results should encourage dental practioners using the TAS-20 in clinical practice, to screen TMD, facial or head pain patients for alexithymia and could also help treating alexithymic TMD, facial or head pain patients.

Third molars and periodontal damage of second molars in the general population.

AIM: The aim of this study was to clarify the association between impacted or erupted third molars and periodontal pathology, assessed by probing depth (PD) and clinical attachment levels (CAL), in adjacent second molars. MATERIALS AND METHODS: Data from the population-based Study of Health in Pomerania (SHIP) was used. This is the first project with whole-body magnetic resonance imaging (WB-MRI) application in a general population setting with dental issues. Calibrated and licensed dentists measured PD and CAL with a periodontal probe. RESULTS: In the mandible, individuals with erupted third molars had a 1.45-fold higher odds ratio (CI:1.03; 2.05; p = 0.031) and individuals with impacted third molars had a 2.37-fold higher odds ratio (CI:1.45; 3.85; p < 0.001) to have higher PD values in the adjacent distal site of second molar than individuals with missing third molars in the total population. These significant associations were even more pronounced in the population free of periodontitis disease. In participants with periodontitis in the maxilla, there was an association of erupted third molars with an increased PD of adjacent molars. CONCLUSION: In particular, in the mandible, those findings could guide dental practitioners more in the direction to remove the third molars after having evaluated the periodontium of the adjacent teeth.

Shank3 Is Part of a Zinc-Sensitive Signaling System That Regulates Excitatory Synaptic Strength.

UNLABELLED: Shank3 is a multidomain scaffold protein localized to the postsynaptic density of excitatory synapses. Functional studies in vivo and in vitro support the concept that Shank3 is critical for synaptic plasticity and the trans-synaptic coupling between the reliability of presynaptic neurotransmitter release and postsynaptic responsiveness. However, how Shank3 regulates synaptic strength remains unclear. The C terminus of Shank3 contains a sterile alpha motif (SAM) domain that is essential for its postsynaptic localization and also binds zinc, thus raising the possibility that changing zinc levels modulate Shank3 function in dendritic spines. In support of this hypothesis, we find that zinc is a potent regulator of Shank3 activation and dynamics in rat hippocampal neurons. Moreover, we show that zinc modulation of synaptic transmission is Shank3 dependent. Interestingly, an autism spectrum disorder (ASD)-associated variant of Shank3 (Shank3(R87C)) retains its zinc sensitivity and supports zinc-dependent activation of AMPAR-mediated synaptic transmission. However, elevated zinc was unable to rescue defects in trans-synaptic signaling caused by the R87C mutation, implying that trans-synaptic increases in neurotransmitter release are not necessary for the postsynaptic effects of zinc. Together, these data suggest that Shank3 is a key component of a zinc-sensitive signaling system, regulating synaptic strength that may be impaired in ASD. SIGNIFICANCE STATEMENT: Shank3 is a postsynaptic protein associated with neurodevelopmental disorders such as autism and schizophrenia. In this study, we show that Shank3 is a key component of a zinc-sensitive signaling system that regulates excitatory synaptic transmission. Intriguingly, an autism-associated mutation in Shank3 partially impairs this signaling system. Therefore, perturbation of zinc homeostasis may impair, not only synaptic functionality and plasticity, but also may lead to cognitive and behavioral abnormalities seen in patients with psychiatric disorders.

Triterpenes for Well-Balanced Scar Formation in Superficial Wounds.

Triterpenes are demonstrably effective for accelerating re-epithelialisation of wounds and known to improve scar formation for superficial lesions. Among the variety of triterpenes, betuline is of particular medical interest. Topical betuline gel (TBG) received drug approval in 2016 from the European Commission as the first topical therapeutic agent with the proven clinical benefit of accelerating wound healing. Two self-conducted randomized intra-individual comparison clinical studies with a total of 220 patients involved in TBG treatment of skin graft surgical wounds have been screened for data concerning the aesthetic aspect of wound healing. Three months after surgery wound treatment with TBG resulted in about 30% of cases with more discreet scars, and standard of care in about 10%. Patients themselves appreciate the results of TBG after 3 months even more (about 50%) compared to standard of care (about 10%). One year after surgery, the superiority of TBG counts for about 25% in comparison with about 10%, and from the patients' point of view, for 25% compared to 4% under standard of care. In the majority of wound treatment cases, there is no difference visible between TBG treatment and standard of care after 1 year of scar formation. However, in comparison, TBG still offers a better chance for discreet scars and therefore happens to be superior in good care of wounds.

Makorin ring zinc finger protein 1 (MKRN1), a novel poly(A)-binding protein-interacting protein, stimulates translation in nerve cells.

The poly(A)-binding protein (PABP), a key component of different ribonucleoprotein complexes, plays a crucial role in the control of mRNA translation rates, stability, and subcellular targeting. In this study we identify RING zinc finger protein Makorin 1 (MKRN1), a bona fide RNA-binding protein, as a binding partner of PABP that interacts with PABP in an RNA-independent manner. In rat brain, a so far uncharacterized short MKRN1 isoform, MKRN1-short, predominates and is detected in forebrain nerve cells. In neuronal dendrites, MKRN1-short co-localizes with PABP in granule-like structures, which are morphological correlates of sites of mRNA metabolism. Moreover, in primary rat neurons MKRN1-short associates with dendritically localized mRNAs. When tethered to a reporter mRNA, MKRN1-short significantly enhances reporter protein synthesis. Furthermore, after induction of synaptic plasticity via electrical stimulation of the perforant path in vivo, MKRN1-short specifically accumulates in the activated dendritic lamina, the middle molecular layer of the hippocampal dentate gyrus. Collectively, these data indicate that in mammalian neurons MKRN1-short interacts with PABP to locally control the translation of dendritic mRNAs at synapses.

The RNA-binding protein MARTA2 regulates dendritic targeting of MAP2 mRNAs in rat neurons.

Dendritic targeting of mRNAs encoding the microtubule-associated protein 2 (MAP2) in neurons involves a cis-acting dendritic targeting element. Two rat brain proteins, MAP2-RNA trans-acting protein (MARTA)1 and MARTA2, bind to the cis-element with both high affinity and specificity. In this study, affinity-purified MARTA2 was identified as orthologue of human far-upstream element binding protein 3. In neurons, it resides in somatodendritic granules and dendritic spines and associates with MAP2 mRNAs. Expression of a dominant-negative variant of MARTA2 disrupts dendritic targeting of endogenous MAP2 mRNAs, while not noticeably altering the level and subcellular distribution of polyadenylated mRNAs as a whole. Finally, MAP2 transcripts associate with the microtubule-based motor KIF5 and inhibition of KIF5, but not cytoplasmic dynein function disrupts extrasomatic trafficking of MAP2 mRNA granules. Thus, in neurons MARTA2 appears to represent a key trans-acting factor involved in KIF5-mediated dendritic targeting of MAP2 mRNAs.

Impact of depressive symptoms on prosthetic status--results of the study of health in Pomerania (SHIP).

OBJECTIVES: Previous investigations have confirmed that every fifth dental patient suffers from clinically significant depressive symptoms. However, the putative impact of depressive symptoms on the prosthetic status has not been addressed in these studies. The objective of this study was to investigate the association between depressive symptoms and prosthetic status based on data from the Study of Health in Pomerania (SHIP-0). METHODS: Data from 2,135 participants aged 30 to 59 years were analyzed. A classification (six classes regarding the number and position of missing teeth per jaw) was used to identify the degree of prosthetic status (no/suboptimal/optimal tooth replacement). The presence of depressive symptoms was assessed with a modified version of von Zerssen's complaints scale. Screening for lifetime diagnoses of mental disorders was performed with the Composite International Diagnostic-Screener (CID-S). Multivariable logistic regressions including several confounders were calculated. RESULTS: A significant protective dose-response effect of depressive symptoms on prosthetic status was found only in men for the lower jaw [0-1 depressive symptoms: odds ratio (OR) = 3.84, 95 % confidence interval (CI, 1.65-8.92), p < 0.01; 2-3: OR = 2.87 (CI, 1.22-6.74), p < 0.05; reference, ≥8; adjusted for age, school education, smoking status, household income, marital status, living without a partner, risky alcohol consumption, obesity, diabetes, and physical activity]. There was no such association in women or for the upper jaw. The analyses using the CID-S confirmed these results. CONCLUSIONS: In the lower jaw, men with depressive symptoms had a better prosthetic status than men without depressive symptoms suggesting a higher level of concern regarding their personal health. CLINICAL RELEVANCE: If dentists might have an opportunity to identify men with depressive symptoms they can provide a wide range of treatment options that may enhance patients' self-esteem and contribute to the patient' well-being. Furthermore, depressive symptoms could indicate a discrepancy between self-perception of the dental health and the actual status which influence the dentists' treatment decision making.

Refining definitions of periodontal disease and caries for prediction models of incident tooth loss.

AIM: To assess the suitability of different definitions of caries and periodontitis for inclusion in tooth loss prediction models. MATERIALS AND METHODS: The Study of Health in Pomerania (SHIP) is a population-based cohort study conducted in 1997-2001 (SHIP-0) and 2002-2006 (SHIP-1). This sample comprised 2,780 subjects aged 20-81 years with complete information on dental and periodontal status [DMFS status, clinical attachment loss (CAL) and probing depth (PD)]. Analyses on five-year tooth loss were limited to half-mouth data. RESULTS: The predictive value of tested definitions was markedly age- and gender-dependent: in 20-39-aged men, the number of decayed or filled surfaces best predicted the number of lost teeth, whereas in young women CAL≥4 mm performed best. In older subjects, periodontal definitions were superior to caries definitions: mean CAL performed best in 40-59-year olds, whereas AL- or PD-related definitions predicted best in 60-81-year olds. On tooth level, mean CAL was the superior definition to assess 5-year incident tooth loss in all strata except for young men. CONCLUSIONS: Caries parameters best predicted incident tooth loss in men aged 20-39 years; in the intermediate and oldest age group and in young women, mean AL was most informative. Therefore, prediction models need to be developed for different age and gender groups.

Dendritic mRNA targeting and translation.

Selective targeting of specific mRNAs into neuronal dendrites and their locally regulated translation at particular cell contact sites contribute to input-specific synaptic plasticity. Thus, individual synapses become decision-making units, which control gene expression in a spatially restricted and nucleus-independent manner. Dendritic targeting of mRNAs is achieved by active, microtubule-dependent transport. For this purpose, mRNAs are packaged into large ribonucleoprotein (RNP) particles containing an array of trans-acting RNA-binding proteins. These are attached to molecular motors, which move their RNP cargo into dendrites. A variety of proteins may be synthesized in dendrites, including signalling and scaffold proteins of the synapse and neurotransmitter receptors. In some cases, such as the alpha subunit of the calcium/calmodulin-dependent protein kinase II (αCaMKII) and the activity-regulated gene of 3.1 kb (Arg3.1, also referred to as activity-regulated cDNA, Arc), their local synthesis at synapses can modulate long-term changes in synaptic efficiency. Local dendritic translation is regulated by several signalling cascades including Akt/mTOR and Erk/MAP kinase pathways, which are triggered by synaptic activity. More recent findings show that miRNAs also play an important role in protein synthesis at synapses. Disruption of local translation control at synapses, as observed in the fragile X syndrome (FXS) and its mouse models and possibly also in autism spectrum disorders, interferes with cognitive abilities in mice and men.

Shank1 mRNA: dendritic transport by kinesin and translational control by the 5'untranslated region.

Dendritic mRNA transport coupled with local regulation of translation enables neurons to selectively alter the protein composition of individual postsynaptic sites. We have analyzed dendritic localization of shank1 mRNAs; shank proteins (shank1-3) are scaffolding molecules of the postsynaptic density (PSD) of excitatory synapses, which are crucial for PSD assembly and the formation of dendritic spines. Live cell imaging demonstrates saltatory movements of shank1 mRNA containing granules along microtubules in both anterograde and retrograde directions. A population of brain messenger ribonucleoprotein particles (mRNPs) containing shank1 mRNAs associates with the cargo-binding domain of the motor protein KIF5C. Through expression of dominant negative proteins, we show that dendritic targeting of shank1 mRNA granules involves KIF5C and the KIF5-associated RNA-binding protein staufen1. While transport of shank1 mRNAs follows principles previously outlined for other dendritic transcripts, shank1 mRNAs are distinguished by their translational regulation. Translation is strongly inhibited by a GC-rich 5(')untranslated region; in addition, internal ribosomal entry sites previously detected in other dendritic transcripts are absent in the shank1 mRNA. A concept emerges from our data in which dendritic transport of different mRNAs occurs collectively via a staufen1- and KIF5-dependent pathway, whereas their local translation is controlled individually by unique cis-acting elements.

On BC1 RNA and the fragile X mental retardation protein.

The fragile X mental retardation protein (FMRP), the functional absence of which causes fragile X syndrome, is an RNA-binding protein that has been implicated in the regulation of local protein synthesis at the synapse. The mechanism of FMRP's interaction with its target mRNAs, however, has remained controversial. In one model, it has been proposed that BC1 RNA, a small non-protein-coding RNA that localizes to synaptodendritic domains, operates as a requisite adaptor by specifically binding to both FMRP and, via direct base-pairing, to FMRP target mRNAs. Other models posit that FMRP interacts with its target mRNAs directly, i.e., in a BC1-independent manner. Here five laboratories independently set out to test the BC1-FMRP model. We report that specific BC1-FMRP interactions could be documented neither in vitro nor in vivo. Interactions between BC1 RNA and FMRP target mRNAs were determined to be of a nonspecific nature. Significantly, the association of FMRP with bona fide target mRNAs was independent of the presence of BC1 RNA in vivo. The combined experimental evidence is discordant with a proposed scenario in which BC1 RNA acts as a bridge between FMRP and its target mRNAs and rather supports a model in which BC1 RNA and FMRP are translational repressors that operate independently.