Slit Homolog Research Articles

Administration of Slit2 analogs to minimize vascular injuries, inflammation, and kidney involvement in β-thalassemia: A hypothesis

Patients with β-thalassemia experience various complications, including vascular damage, inflammation, and kidney dysfunction. Although antiplatelet and chelation therapies help reduce these complications, more targeted treatment is needed to enhance therapeutic efficacy and improve patient prognosis. Slit homolog 2 (Slit2) is a secreted extracellular matrix glycoprotein. Upon binding to their cognate roundabout (Robo) receptors expressed on platelets, leukocytes, and endothelial cells, Slit2-Robo complexes activate multiple downstream signaling pathways. Accumulating evidence suggests that Slit2-Robo signaling inhibits platelet adhesion and spreading. Slit2-Robo signaling decreases leukocyte migration and proinflammatory cytokine release and can be modulated by Slit2 analogs. Therefore, we hypothesized that the administration of Slit2 might help minimize vascular injury, inflammation, and kidney dysfunction-related complications in patients with β-thalassemia. Our proposed idea provides a deeper understanding of the pathophysiology of β-thalassemia, and modulation of the Slit2-Robo signaling cascade could serve as an alternative therapy in the future, pending validation.

Slit2 suppresses endotoxin-induced uveitis by inhibiting the PI3K/Akt/IKK/NF-κB pathway.

Uveitis is a devastating intraocular inflammatory disease. The secreted leucine-rich repeat protein slit homologue 2 (Slit2) has been found to be an essential regulator of inflammation. This study aimed to analyse the anti-inflammatory effects and the underlying mechanisms of Slit2 in an endotoxin-induced uveitis (EIU) rat model. In this study, rats with EIU pretreated recombinant human Slit2 (rhSlit2) or a control vehicle by intravitreal injection. The clinical scores were graded under a slit lamp. The protein concentrations and total number of cells in the aqueous humour (AqH) were examined, and the retinal expression of various inflammatory mediators was detected. The levels of nuclear factor-kappa B (NF-κB), phosphorylated NF-κB, IkappaB-a (IκB-a), phosphorylated IκB-a, IKK, phosphorylated IKK, PI3Kp85, phosphorylated PI3Kp85, Akt and phosphorylated Akt were evaluated by western blotting. Treatment with rhSlit2 dramatically diminished the clinical scores of EIU, with significant decreases in inflammatory cell infiltration, protein concentrations, cellulose-like exudates, the production of ICAM-1, MCP-1, TNF-α and IL-6 in the AqH; and adhesion of leucocytes. The PI3K/Akt/IKK/NF-κB pathway was found to be activated in EIU. However, the pre-treatment of rhSlit2 significantly inhibited the production of ICAM-1, MCP-1, TNF-α, and IL-6, and inhibited leucocyte adhesion by modulating the PI3K/Akt/IKK/NF-κB pathway. In conclusion, the intravitreal injection of rhSlit2 alleviated EIU-related inflammation in Sprague-Dawley rats by reducing the proinflammatory cytokines and leucocyte adhesion; in particular, rhSlit2 may inhibit LPS-induced inflammation by inhibiting the activation of PI3K/Akt/IKK/NF-κB signalling pathway. Therefore, rhSlit2 shows significant potential for effectively alleviating immune inflammatory responses in vivo.

Cognitive stimulation in the workplace, plasma proteins, and risk of dementia: three analyses of population cohort studies

ObjectivesTo examine the association between cognitively stimulating work and subsequent risk of dementia and to identify protein pathways for this association.DesignMulticohort study with three sets of analyses.SettingUnited Kingdom, Europe, and...

Overexpression of Slit2 decreases neuronal excitotoxicity, accelerates glymphatic clearance, and improves cognition in a multiple microinfarcts model

BackgroundCerebral microinfarcts (MIs) lead to progressive cognitive impairments in the elderly, and there is currently no effective preventative strategy due to uncertainty about the underlying pathogenic mechanisms. One possibility is the dysfunction of GABAergic transmission and ensuing excitotoxicity. Dysfunction of GABAergic transmission induces excitotoxicity, which contributes to stroke pathology, but the mechanism has kept unknown. The secreted leucine-rich repeat (LRR) family protein slit homologue 2 (Slit2) upregulates GABAergic activity and protects against global cerebral ischemia, but the neuroprotective efficacy of Slit2 against MIs has not been examined.MethodsMiddle-aged Wild type (WT) and Slit2-Tg mice were divided into sham and MI treatment groups. MIs were induced in parietal cortex by laser-evoked arteriole occlusion. Spatial memory was then compared between sham and MI groups using the Morris water maze (MWM) task. In addition, neuronal activity, blood brain barrier (BBB) permeability, and glymphatic clearance in peri-infarct areas were compared using two-photon imaging, while GABAergic transmission, microglial activation, neuronal loss, and altered cortical connectivity were compared by immunofluorescent staining or western blotting.ResultsMicroinfarcts increased the amplitude and frequency of spontaneous intracellular Ca2+ signals, reduced neuronal survival and connectivity within parietal cortex, decreased the number of GABAergic interneurons and expression of vesicular GABA transporter (VGAT), induced neuroinflammation, and impaired both glymphatic clearance and spatial memory. Alternatively, Slit2 overexpression attenuated dysfunctional neuronal Ca2+ signaling, protected against neuronal death in the peri-infarct area as well as loss of parietal cortex connectivity, increased GABAergic interneuron number and VGAT expression, attenuated neuroinflammation, and improved both glymphatic clearance and spatial memory.ConclusionOur results strongly suggest that overexpression of Slit2 protected against the dysfunction in MIs, which is a potential therapeutic target for cognition impairment in the elderly.

ROBO1 Expression in Metastasizing Breast and Ovarian Cancer: SLIT2-induced Chemotaxis Requires Heparan Sulfates (Heparin).

The members of the slit homolog (SLIT) and roundabout homolog (ROBO) families have emerged as important signaling molecules in tumor metastasis. This study analyzed their role in regulating breast cancer (BC) cell motility and chemotaxis and assessed expression of ROBO1 in brain metastases (BMs) of breast, lung, and colon cancer, and in peritoneal metastases (PMs) of ovarian cancer. The BC cell line MDA-MB231 was subjected to scratch, motility, and chemotaxis assays using heparin and a purified recombinant N-terminal SLIT2 fragment. Protein expression was assessed in primary tumors and metastases by immunohistochemistry. Exposure to SLIT2 induced MDA-MB231 cell motility, but no significant chemotaxis without the presence of heparin. ROBO1 was expressed in 4/5 primary BC and in 18/21 BC-derived BM samples; 7/9 BM primary lung cancer samples also stained positive. In contrast, BMs from colorectal cancer were negative for ROBO1. Primary ovarian cancer and ovarian PM showed ROBO1 expression in 0/6 and in only 2/6 samples, respectively, whereas SLIT2 was observed in 1/6 primary cancer and in 6/6 PMs samples. SLIT2 can induce BC cell motility and chemotaxis, but the latter requires the presence of heparin. BM expression of ROBO1 is a common feature of some, but not all cancer types. SLIT2 expression appears to be a general feature of ovarian cancer-derived PMs.

387 The Effect of Slit homolog 2 (SLIT2) on Populations of Preantral Follicles in Cultured Cortical Tissue from Pig Ovaries.

387 The Effect of Slit homolog 2 (SLIT2) on Populations of Preantral Follicles in Cultured Cortical Tissue from Pig Ovaries.

Down-regulation of N-deacetylase-N-sulfotransferase-1 signaling in the developing diaphragmatic vasculature of nitrofen-induced congenital diaphragmatic hernia

BackgroundCongenital diaphragmatic hernia (CDH) has been attributed to various developmental abnormalities of the underlying tissue components. N-deacetylase-N-sulfotransferase-1 (Ndst1) is a strongly expressed biosynthetic enzyme in endothelial cells, which has recently been identified as an important factor during diaphragmatic vascularization. Loss of endothelial Ndst1 has been demonstrated to cause angiogenic defects in the developing diaphragm and disrupt normal diaphragmatic development. Furthermore, deficiency of Ndst1 diminishes the expression of slit homolog 3 (Slit3), a known CDH-related gene that has been associated with reduced vascular density and muscle defects in the diaphragm of Slit3−/− mice. We hypothesized that expression of Ndst1 and Slit3 is decreased in the diaphragmatic vasculature of fetal rats with nitrofen-induced CDH. MethodsTime-mated rats received either nitrofen or vehicle on gestational day 9 (D9). Fetal diaphragms were microdissected on D13, D15 and D18, and divided into control and nitrofen-exposed specimens. Gene expression levels of Ndst1 and Slit3 were assessed using qRT-PCR. Immunofluorescence-double-staining for Ndst1 and Slit3 was performed to evaluate protein expression and localization. ResultsRelative mRNA expression of Ndst1 and Slit3 was significantly decreased in pleuroperitoneal folds (D13), developing diaphragms (D15) and fully muscularized diaphragms (D18) of nitrofen-exposed fetuses compared to controls. Confocal-laser-scanning-microscopy revealed markedly diminished Ndst1 and Slit3 expression in endothelial cells within the diaphragmatic vasculature on D13, D15 and D18 compared to controls. ConclusionsDown-regulation of Ndst1 signaling in the developing diaphragm may impair endothelial cell migration and angiogenesis, thus leading to defective diaphragmatic vascular development and CDH. Level of evidenceIb

Slit2 suppresses endothelial cell proliferation and migration by inhibiting the VEGF-Notch signaling pathway.

Slit homolog 2 (Slit2) is distributed in various tissues and participates in numerous cellular processes; however, the role of Slit2 in the regulation of angiogenesis remains controversial, since it has previously been reported to exert proangiogenic and antiangiogenic activities. The present study aimed to investigate the effects of Slit2 on vascular endothelial cell proliferation and migration in vitro, and to reveal the possible underlying signaling pathway. Aortic endothelial cells were isolated from Sprague Dawley rats and cultured. Cell proliferation assay, cell migration assay, immunocytochemistry and small interfering RNA transfection were subsequently performed. The results demonstrated that exogenous Slit2 administration markedly suppressed TNF-α-induced endothelial cell proliferation and migration in vitro. In addition, TNF-α application upregulated the protein expression levels of vascular endothelial growth factor (VEGF) and Notch in RAECs, whereas Slit2 administration downregulated VEGF and Notch expression in RAECs cultured in TNF-α conditioned medium. Further studies indicated that knockdown of VEGF suppressed the effects of TNF-α on the induction of RAEC proliferation and migration. VEGF knockdown-induced inhibition of RAEC proliferation and migration in TNF-α conditioned medium was also achieved without Slit2 administration. Furthermore, VEGF knockdown markedly decreased Notch1 and Notch2 expression. These results indicated that Slit2 suppresses TNF-α-induced vascular endothelial cell proliferation and migration in vitro by inhibiting the VEGF-Notch signaling pathway. Therefore, Slit2 may inhibit the proliferation and migration of endothelial cells during vascular development.

The Caenorhabditis elegans NF2/Merlin Molecule NFM-1 Nonautonomously Regulates Neuroblast Migration and Interacts Genetically with the Guidance Cue SLT-1/Slit.

During nervous system development, neurons and their progenitors migrate to their final destinations. In Caenorhabditis elegans, the bilateral Q neuroblasts and their descendants migrate long distances in opposite directions, despite being born in the same posterior region. QR on the right migrates anteriorly and generates the AQR neuron positioned near the head, and QL on the left migrates posteriorly, giving rise to the PQR neuron positioned near the tail. In a screen for genes required for AQR and PQR migration, we identified an allele of nfm-1, which encodes a molecule similar to vertebrate NF2/Merlin, an important tumor suppressor in humans. Mutations in NF2 lead to neurofibromatosis type II, characterized by benign tumors of glial tissues. Here we demonstrate that in C. elegans, nfm-1 is required for the ability of Q cells and their descendants to extend protrusions and to migrate, but is not required for direction of migration. Using a combination of mosaic analysis and cell-specific expression, we show that NFM-1 is required nonautonomously, possibly in muscles, to promote Q lineage migrations. We also show a genetic interaction between nfm-1 and the C. elegans Slit homolog slt-1, which encodes a conserved secreted guidance cue. Our results suggest that NFM-1 might be involved in the generation of an extracellular cue that promotes Q neuroblast protrusion and migration that acts with or in parallel to SLT-1 In vertebrates, NF2 and Slit2 interact in axon pathfinding, suggesting a conserved interaction of NF2 and Slit2 in regulating migratory events.

Slit2‑Robo1 signaling promotes the adhesion, invasion and migration of tongue carcinoma cells via upregulating matrix metalloproteinases 2 and 9, and downregulating E‑cadherin.

Whether Slit homologue 2 (Slit2) inhibits or promotes tumor cell migration remains controversial, and the role of Slit2-Roundabout 1 (Robo1) signaling in oral cancer remains to be fully elucidated. The aim of the present study was to investigate the role of Slit2-Robo1 signaling in the adhesion, invasion and migration of tongue carcinoma cells, and the mechanism by which Slit2-Robo1 signaling inhibits or promotes tumor cell migration. Tca8113 tongue carcinoma cells were treated with the monoclonal anti-human Robo1 antibody, R5, to inhibit the Slit2-Robo1 signaling pathway, with immunoglobulin (Ig)G2b treatment as a negative control. The expression levels of Slit2 and Robo1 were determined using flow cytometry. The effects of R5 on the adhesion, invasion and migration of Tca8113 tongue carcinoma cells were investigated. Gelatin zymography was used to investigate the activity of matrix metalloproteinase 2 (MMP2) and MMP9. Western blot analysis was used to evaluate the expression levels of E-cadherin in Tca8113 cells treated with 10 µg/ml of either R5 or IgG2b. Slit2 and Robo1 proteins were found to be expressed in the Tca8113 cells. R5 significantly inhibited the adhesion, invasion and migration of Tca8113 cells in vitro. R5 also inhibited the activities of MMP2 and MMP9, and increased the expression of E-cadherin in the Tca8113 cells. These results suggested that Slit2-Robo1 signaling promoted the adhesion, invasion and migration of tongue carcinoma cells by upregulating the expression levels of MMP2 and MMP9 and, downregulating the expression of E-cadherin.

Analysis of gene expression during aging of CGNs in culture: implication of SLIT2 and NPY in senescence.

Senescence is the major key factor that leads to the loss of neurons throughout aging. Cellular senescence is not the consequence of single cause, but there are multiple aspects which may induce senescence in a cell. Various causes such as gene expression, molecular interactions and protein processing and chromatin organization are described as causal factor for senescence. It is well known that the damage to the nuclear or mitochondrial DNA contributes to the aging either directly by inducing the apoptosis/cellular senescence or indirectly by altering cellular functions. The significant nuclear DNA damage with the age is directly associated with the continuous declining in DNA repair. The continuous decline in expression of topoisomerase 2 beta (Topo IIβ) in cultured cerebellar granule neurons over time indicated the decline in the repair of damage DNA. DNA Topo IIβ is an enzyme that is crucial for solving topological problems of DNA and thus has an important role in DNA repair. The enzyme is predominantly present in non-proliferating cells such as neurons. In this paper, we have studied the genes which were differentially expressed over time in cultured cerebellar granule neurons (CGNs) and identified potential genes associated with the senescence. Our results showed that the two genes neuropeptide Y (Npy) and Slit homolog 2 (Drosophila) (Slit2) gradually increase during aging, and upon suppression of these two genes, there was gradual increase in cell viability along with restoration of the expression of Topo IIβ and potential repair proteins.

Genetic Variation Predicts Serum Lycopene Concentrations in a Multiethnic Population of Postmenopausal Women ,

Background: The consumption and blood concentrations of lycopene are both positively and inversely associated with the risk of several chronic diseases. The inconsistences in lycopene disease association studies may stem from a lack of knowledge about the genetic variation in the synthesis, metabolism, and deposition of transport and binding proteins, which potentially influence serum lycopene concentrations.Objective: We examined the association between variation across the genome and serum concentrations of lycopene in a multiethnic population.Methods: Participants included African (n = 914), Hispanic (n = 464), and European (n = 1203) American postmenopausal women from the Women’s Health Initiative. We analyzed ∼7 million single nucleotide polymorphisms (SNPs). Linear regression models were used to assess associations between each SNP and serum concentrations (log transformed, continuous) of lycopene; we adjusted for age, body mass index, and population substructure. Models were run separately by ethnicity, and results were combined in a transethnic fixed-effects meta-analysis.Results: In the meta-analysis, the scavenger receptor class B, member 1 (SCARB1) gene, which encodes for a cholesterol membrane transporter, was significantly associated with lycopene concentrations (rs1672879; P < 2.68 × 10−9). Each additional G allele resulted in a 12% decrease in lycopene concentrations for African Americans, 20% decrease for Hispanic Americans, and 9% decrease for European Americans. In addition, 2 regions were significantly associated with serum lycopene concentrations in African Americans: the slit homolog 3 gene (SLIT3), which serves as a molecular guidance cue in cellular migration, and the dehydrogenase/reductase (SDR family) member 2 (DHRS2) gene, which codes for an oxidoreductase that mitigates the breakdown of steroids.Conclusions: We found 3 novel loci associated with serum lycopene concentrations, 2 of which were specific to African Americans. Future functional studies looking at these specific genes may provide insight into the metabolism and underlying function of lycopene in humans, which may further elucidate lycopene’s influence on disease risk and health. This trial was registered at clinicaltrials.gov as NCT00000611.

MiR-218 inhibits the migration and invasion of glioma U87 cells through the Slit2-Robo1 pathway.

Malignant gliomas are the most common primary brain tumors in adults and are associated with the highest mortality rate. Glioma invasion is one of the most notable causes of the poor prognosis of this cancer. Preventing the invasive behavior of malignant glioma cells by altering effector molecules can significantly improve the prognosis of a patient. microRNAs (miRNAs) are small noncoding RNAs, ~22 nucleotides in length, that are able to function as oncogenes or tumor suppressors in human cancer. In the present study, the expression level of miRNA 218 (miR-218) was found to be markedly downregulated in glioma cell lines and human primary glioma tissues. miR-218 upregulation was found to dramatically reduce the migratory speed and invasive ability of glioma cells. Furthermore, it was demonstrated that ectopic expression of miR-218 in glioma cells resulted in the downregulation of roundabout, axon guidance receptor, homolog 1 (Robo1), upregulation of Slit homolog 2 (Slit2) and the expression of associated proteins following Robo1 knockdown by small interfering RNA. In addition, it was demonstrated that miR-218 inactivated the Slit2-Robo1 pathway through downregulating Robo1 expression by directly targeting the 3′-untranslated region (3′-UTR) of Robo1. The present results indicate that miR-218 plays important roles in preventing the invasiveness of glioma cells, and reveals a novel mechanism of miRNA-mediated direct suppression of the Slit2-Robo1 pathway in glioma.

Identification of polymorphisms associated with production traits on chicken (Gallus gallus) chromosome 4.

Genetic selection for production traits has resulted in a rapid improvement in animal performance and development. Previous studies have mapped quantitative trait loci for body weight at 35 and 41 days, and drum and thigh yield, onto chicken chromosome 4. We investigated this region for single nucleotide polymorphisms and their associations with important economic traits. Three positional candidate genes were studied: KLF3 (Krüeppel-like factor 3), SLIT2 (Slit homolog 2), and PPARGC1A (peroxisome proliferator-activated receptor gamma, coactivator 1 alpha). Fragment sequencing of these genes was conducted in 11 F1 animals, and one polymorphism in each gene was selected and genotyped in an F2 population (N = 276) and a paternal broiler line TT (N = 840). Associations were identified with growth, carcass, and fat traits in the F2 and the paternal line (P < 0.05). Using single markers in both the F2 and the TT line, KLF3 was associated with weight gain (P < 0.05), PPPARGC1A was associated with liver and wing-parts weights and yields (P < 0.05), and SLIT2 was associated with back yield (P < 0.05) and fat traits (P < 0.05). Using multiple markers, KLF3 lost its significance in both populations, and SLIT2 was associated with feed conversion only in the TT population (P < 0.05). The QTLs mapped in the F2 population could be partly explained by PPARGC1A and SLIT2, which were associated with body weight at 35 and 41 days, respectively, and with drum and thigh yield in the same population. The results of this study indicate the importance of these genes for production traits.

Heparan sulfate deficiency disrupts developmental angiogenesis and causes congenital diaphragmatic hernia

Congenital diaphragmatic hernia (CDH) is a common birth malformation with a heterogeneous etiology. In this study, we report that ablation of the heparan sulfate biosynthetic enzyme NDST1 in murine endothelium (Ndst1ECKO mice) disrupted vascular development in the diaphragm, which led to hypoxia as well as subsequent diaphragm hypoplasia and CDH. Intriguingly, the phenotypes displayed in Ndst1ECKO mice resembled the developmental defects observed in slit homolog 3 (Slit3) knockout mice. Furthermore, introduction of a heterozygous mutation in roundabout homolog 4 (Robo4), the gene encoding the cognate receptor of SLIT3, aggravated the defect in vascular development in the diaphragm and CDH. NDST1 deficiency diminished SLIT3, but not ROBO4, binding to endothelial heparan sulfate and attenuated EC migration and in vivo neovascularization normally elicited by SLIT3-ROBO4 signaling. Together, these data suggest that heparan sulfate presentation of SLIT3 to ROBO4 facilitates initiation of this signaling cascade. Thus, our results demonstrate that loss of NDST1 causes defective diaphragm vascular development and CDH and that heparan sulfate facilitates angiogenic SLIT3-ROBO4 signaling during vascular development.

Regulation of UHRF1 by miR‐146a/b modulates gastric cancer invasion and metastasis

Epigenetic changes play significant roles in the development of cancer. UHRF1, as an epigenetic regulator, has been shown to be overexpressed and to coordinate tumor suppressor gene silencing in several cancers. However, the role and underlying mechanism of UHRF1 in gastric cancer (GC) progression remain largely unknown. In this study, we investigated the expression and function of UHRF1 in GC metastasis and explored its upstream regulatory mechanisms at the microRNA level. UHRF1 was overexpressed in GC tissues, especially in metastatic ones, and a high level of UHRF1 expression predicted poor survival. The down-regulation of UHRF1 suppressed GC invasion and metastasis in vitro and in vivo. We identified and verified miR-146a and miR-146b as direct upstream regulators of UHRF1. Furthermore, the restoration of miR-146a/b dramatically reduced the expression of UHRF1 through the direct targeting of its 3'-UTR, and this effect in turn reactivated the slit homologue 3 (Slit3), cadherin 4 (CDH4), and runt-related transcription factor 3 (RUNX3) genes via promoter demethylation. Finally, analyses of miR-146a/b and UHRF1 levels in human GC tissues revealed that miR-146a/b correlated inversely with UHRF1 expression. These findings describe a new mechanism for the regulation of UHRF1 and aberrant DNA hypermethylation in GC. The newly identified miR-146a/b/UHRF1 axis provides insight into the GC metastasis process, and targeting this novel axis represents a therapeutic approach to blocking GC metastasis.

SDF-1–CXCR4 differentially regulates autoimmune diabetogenic T cell adhesion through ROBO1–SLIT2 interactions in mice

We had previously reported that stromal cell-derived factor 1 (SDF-1) mediates chemorepulsion of diabetogenic T cell adhesion to islet microvascular endothelium through unknown mechanisms in NOD mice. Here we report that SDF-1-mediated chemorepulsion occurs through slit homologue (SLIT)2-roundabout, axon guidance receptor, homologue 1 (Drosophila) (ROBO1) interactions. C-X-C receptor (CXCR)4 and ROBO1 protein expression was measured in mouse and human T cells. Parallel plate flow chamber adhesion and detachment studies were performed to examine the molecular importance of ROBO1 and SLIT2 for SDF-1-mediated T cell chemorepulsion. Diabetogenic splenocyte transfer was performed in NOD/LtSz Rag1(-/-) mice to examine the effect of the SDF-1 mimetic CTCE-0214 on adoptive transfer of diabetes. CXCR4 and ROBO1 protein expression was elevated in diabetic NOD/ShiLtJ T cells over time and coincided with the onset of hyperglycaemia. CXCR4 and ROBO1 expression was also increased in human type 1 diabetic T cells, with ROBO1 expression maximal at less than 1 year post diagnosis. Cell detachment studies revealed that immunoneutralisation of ROBO1 prevented SDF-1-mediated chemorepulsion of NOD T cell firm adhesion to TNFα-stimulated islet endothelial cells. SDF-1 increased NOD T cell adhesion to recombinant adhesion molecules, a phenomenon that was reversed by recombinant SLIT2. Finally, we found that an SDF-1 peptide mimetic prevented NOD T cell adhesion in vitro and significantly delayed adoptive transfer of autoimmune diabetes in vivo. These data reveal a novel molecular pathway, which regulates diabetogenic T cell recruitment and may be useful in modulating autoimmune diabetes.

SLIT2 (slit homolog 2 (Drosophila))

Review on SLIT2 (slit homolog 2 (Drosophila)), with data on DNA, on the protein encoded, and where the gene is implicated.

SLIT3 (slit homolog 3 (Drosophila))

Review on SLIT3 (slit homolog 3 (Drosophila)), with data on DNA, on the protein encoded, and where the gene is implicated.

Identification of In Vivo, Conserved, TAF15 RNA Binding Sites Reveals the Impact of TAF15 on the Neuronal Transcriptome

RNA binding proteins (RBPs) have emerged as major causative agents of amyotrophic lateral sclerosis (ALS). To investigate the function of TAF15, an RBP recently implicated in ALS, we explored its target RNA repertoire in normal human brain and mouse neurons. Coupling high-throughput sequencing of immunoprecipitated and crosslinked RNA with RNA sequencing and TAF15 knockdowns, we identified conserved TAF15 RNA targets and assessed the impact of TAF15 on the neuronal transcriptome. We describe a role of TAF15 in the regulation of splicing for a set of neuronal RNAs encoding proteins with essential roles in synaptic activities. We find that TAF15 is required for a critical alternative splicing event of the zeta-1 subunit of the glutamate N-methyl-D-aspartate receptor (Grin1) that controls the activity and trafficking of NR1. Our study uncovers neuronal RNA networks impacted by TAF15 and sets the stage for investigating the role of TAF15 in ALS pathogenesis.