Explore the vast range of titles available.

Autonomic nerve fibres in the tumour microenvironment regulate cancer initiation and dissemination, but how nerves emerge in tumours is currently unknown. Here we show that neural progenitors from the central nervous system that express doublecortin (DCX + ) infiltrate prostate tumours and metastases, in which they initiate neurogenesis. In mouse models of prostate cancer, oscillations of DCX + neural progenitors in the subventricular zone—a neurogenic area of the central nervous system—are associated with disruption of the blood–brain barrier, and with the egress of DCX + cells into the circulation. These cells then infiltrate and reside in the tumour, and can generate new adrenergic neurons. Selective genetic depletion of DCX + cells inhibits the early phases of tumour development in our mouse models of prostate cancer, whereas transplantation of DCX + neural progenitors promotes tumour growth and metastasis. In humans, the density of DCX + neural progenitors is strongly associated with the aggressiveness and recurrence of prostate adenocarcinoma. These results reveal a unique crosstalk between the central nervous system and prostate tumours, and indicate neural targets for the treatment of cancer. In a mouse model of prostate cancer, neural progenitors from the central nervous system that express doublecortin infiltrate tumours and metastases, and can generate new adrenergic neurons in tumours.

Adult hippocampal neurogenesis (AHN) plays an important role in hippocampus-dependent function. The number of doublecortin (Dcx)-positive immature neurons in the dentate gyrus decreases over time, especially in the early stages of Alzheimer’s disease (AD), and is further reduced in later stages of AD. Obesity in midlife is associated with dementia later in life; however, the underlying mechanisms by which obesity results in the development of dementia later in life remain unknown. Here, we show that endoplasmic reticulum (ER) stress was activated in the hippocampus and processes of Dcx-expressing immature neurons were shortened, coexpressing CHOP in APP23 AD model mice with high-fat diet-induced long-term obesity and in aged Lepr db / db ( db / db ) mice. Moreover, in cells differentiating from hippocampal neurospheres, Dcx mRNA was rapidly degraded via a microRNA (miRNA) pathway after thapsigargin treatment in vitro. These results indicate that loss of Dcx mRNA induced by ER stress during AHN may cause memory impairment in obese individuals later in life.

Microtubules form from longitudinally and laterally assembling tubulin α–β dimers. The assembly induces strain in tubulin, resulting in cycles of microtubule catastrophe and regrowth. This ‘dynamic instability’ is governed by GTP hydrolysis that renders the microtubule lattice unstable, but it is unclear how. We used a human microtubule nucleating and stabilizing neuronal protein, doublecortin, and high-resolution cryo-EM to capture tubulin’s elusive hydrolysis intermediate GDP•Pi state, alongside the prehydrolysis analog GMPCPP state and the posthydrolysis GDP state with and without an anticancer drug, Taxol. GTP hydrolysis to GDP•Pi followed by Pi release constitutes two distinct structural transitions, causing unevenly distributed compressions of tubulin dimers, thereby tightening longitudinal and loosening lateral interdimer contacts. We conclude that microtubule catastrophe is triggered because the lateral contacts can no longer counteract the strain energy stored in the lattice, while reinforcement of the longitudinal contacts may support generation of force.

This study investigated the neuroprotective effects of exendin-4 (EXE-4), an analog of the glucagon-like peptide 1 receptor (GLP-1R) on memory and on the neuronal populations that constitute the hippocampus of rats submitted to a sporadic dementia of Alzheimer’s type (SDAT). Male Wistar rats received streptozotocin (STZ icv, 3 mg/kg diluted in aCFS, 5 µl/ventricle) and were treated for 21 days with EXE-4 (10 µg/kg, ip; saline as the vehicle). Four groups were formed: vehicle, EXE-4, STZ, and STZ + EXE-4. The groups were submitted to Y-Maze (YM), object recognition (ORT), and object displacement tasks (ODT) to assess learning and memory. The brains were used for immunohistochemical and immunofluorescent techniques with antibodies to NeuN, cleaved caspase-3 (CC3), PCNA, doublecortin (DCX), synaptophysin (SYP), and insulin receptor (IR). STZ worsened spatial memory in the YMT, as well as short-term (STM) and long-term (LTM) memories in the ORT and ODT, respectively. EXE-4 protected against memory impairment in STZ animals. STZ reduced mature neuron density (NeuN) and increased cell apoptosis (CC3) in the DG, CA1, and CA3. EXE-4 protected against neuronal death in all regions. EXE-4 increased PCNA + cells in all regions of the hippocampus, and STZ attenuated this effect. STZ reduced neurogenesis in DG per se as well as synaptogenesis induced by EXE-4. EXE-4 increased immunoreactivity to IR in the CA1. From these findings, EXE-4 showed a beneficial effect on hippocampal pyramidal and granular neurons in the SDAT showing anti-apoptotic properties and promoting cell proliferation. In parallel, EXE-4 preserved the memory of SDAT rats. EXE-4 appears to enhance synapses at CA3 and DG. In conclusion, these data indicate that agonists to GLP-1R have a beneficial effect on hippocampal neurons in AD.

The dual leucine zipper kinase (DLK) signaling pathway regulates neural development aspects, including axonal growth, neuronal migration, and apoptosis, in diverse model organisms[1-5]. Most DLK-mutant mice exhibit perinatal mortality[6]. DLK induces JNK (c-Jun N-terminal kinase) activity in vitro. In mammals, JNK phosphorylates several target proteins, including those involved in cell movement (DCX)[7]. Studies on vitamin D treatment and primary cultures of murine neural progenitor cells have revealed an increase in DCX-expressing cells[8]. This study, we aimed to determine the effect of vitamin D administration on the expression levels of DCX and phosphorylated DCX proteins involved in development and axon growth through the DLK-MAPK signaling pathway in developing neurons and to identify other proteins that vitamin D may interact with. 10 M 1,25-dihydroxy vitamin D3 and ethanol treatments were administered 24 h after establishing primary cortical neuron cultures from 16-day-old rat embryos. Protein expression levels were analyzed at 24,48,72,96,120, and 144 h post-treatment. VDR-immunoprecipitation (IP) was performed 30 min after treatment to illustrate the rapid response impact. DLK and DCX protein expression levels significantly increased 24 hours after vitamin D treatment compared to the ethanol-treated group (p <0.05 and p <0.001, respectively), while pDCX levels decreased significantly (p <0.01). At 48, 96, and 120 hours post-administration, DLK levels remained significantly elevated in the vitamin D group compared to the control group (p <0.01, p <0.05, and p <0.01, respectively), but showed significant reduction at 72 and 144 hours (p <0.01, p <0.01, respectively). At 72,96, and 120 hours, DCX protein expression was significantly lower in the vitamin D group than in the control group (p <0.001, p <0.01, and p <0.01, respectively).pDCX protein expression levels were significantly reduced at 48, 72, and 96 hours after vitamin D treatment compared to the control group (p <0.05, p <0.01, and p <0.01, respectively). At 120 hours, pDCX expression was significantly higher than in the ethanol-treated and control groups (p <0.05, p <0.05). VDR precipitated with DLK and STMN2 proteins after VDR-Ip. The results of our study suggest that vitamin D administered to newly formed neurons may influence the levels of DLK, DCX, and p-DCX proteins, presumably performing a regulatory role at various phases of development. VDR may interact with DLK and STMN2. This study was supported by the TÜBİTAK 1002-A (Project No:123S438).

Adolescence represents a crucial period for maturation of brain structures involved in cognition. Early in life unhealthy dietary patterns are associated with inferior cognitive outcomes at later ages; conversely, healthy diet is associated with better cognitive results. In this study we analyzed the effects of a short period of hypercaloric diet on newborn hippocampal doublecortin + (DCX) immature neurons in adolescent mice. Male mice received high fat diet (HFD) or control low fat diet (LFD) from the 5th week of age for 1 or 2 weeks, or 1 week HFD followed by 1 week LFD. After diet supply, mice were either perfused for immunohistochemical (IHC) analysis or their hippocampi were dissected for biochemical assays. Detailed morphometric analysis was performed in DCX + cells that displayed features of immature neurons. We report that 1 week-HFD was sufficient to dramatically reduce dendritic tree complexity of DCX + cells. This effect occurred specifically in dorsal and not ventral hippocampus and correlated with reduced BDNF expression levels in dorsal hippocampus. Both structural and biochemical changes were reversed by a return to LFD. Altogether these studies increase our current knowledge on potential consequences of hypercaloric diet on brain and in particular on dorsal hippocampal neuroplasticity.

Glioblastoma (GBM) remains the leading cause of cancer-related deaths with the lowest five-year survival rates among all of the human cancers. Multiple factors contribute to its poor outcome, including intratumor heterogeneity, along with migratory and invasive capacities of tumour cells. Over the last several years Doublecortin (DCX) has been one of the debatable factors influencing GBM cells’ migration. To resolve DCX’s ambiguous role in GBM cells’ migration, we set to analyse the expression patterns of DCX along with Nestin (NES) and Oligodendrocyte lineage transcription factor 2 (OLIG2) in 17 cases of GBM, using immunohistochemistry, followed by an analysis of single-cell RNA-seq data. Our results showed that only a small subset of DCX positive (DCX+) cells was present in the tumour. Moreover, no particular pattern emerged when analysing DCX+ cells relative position to the tumour margin. By looking into single-cell RNA-seq data, the majority of DCX+ cells were classified as non-cancerous, with a small subset of cells that could be regarded as glioma stem cells. In conclusion, our findings support the notion that glioma cells express DCX; however, there is no clear evidence to prove that DCX participates in GBM cell migration.

The feasibility of delivering mitochondria intranasally so as to bypass the blood–brain barrier in treating Parkinson's disease (PD), was evaluated in unilaterally 6-OHDA-lesioned rats. Intranasal infusion of allogeneic mitochondria conjugated with Pep-1 (P-Mito) or unconjugated (Mito) was performed once a week on the ipsilateral sides of lesioned brains for three months. A significant improvement of rotational and locomotor behaviors in PD rats was observed in both mitochondrial groups, compared to sham or Pep-1-only groups. Dopaminergic (DA) neuron survival and recovery > 60% occurred in lesions of the substantia nigra (SN) and striatum in Mito and P-Mito rats. The treatment effect was stronger in the P-Mito group than the Mito group, but the difference was insignificant. This recovery was associated with restoration of mitochondrial function and attenuation of oxidative damage in lesioned SN. Notably, P-Mito suppressed plasma levels of inflammatory cytokines. Mitochondria penetrated the accessory olfactory bulb and doublecortin-positive neurons of the rostral migratory stream (RMS) on the ipsilateral sides of lesions and were expressed in striatal, but not SN DA neurons, of both cerebral hemispheres, evidently via commissural fibers. This study shows promise for intranasal delivery of mitochondria, confirming mitochondrial internalization and migration via RMS neurons in the olfactory bulb for PD therapy.

Stress and glucocorticoid hormones regulate hippocampal neurogenesis, but the molecular mechanisms underlying their effects are unknown. We, therefore, investigated the molecular signaling pathways mediating the effects of cortisol on proliferation, neuronal differentiation, and astrogliogenesis, in an immortalized human hippocampal progenitor cell line. In addition, we examined the molecular signaling pathways activated in the hippocampus of prenatally stressed rats, characterized by persistently elevated glucocorticoid levels in adulthood. In human hippocampal progenitor cells, we found that low concentrations of cortisol (100 nM) increased proliferation (+16%), decreased neurogenesis into microtubule-associated protein 2 (MAP2)-positive neurons (-24%) and doublecortin (Dcx)-positive neuroblasts (-21%), and increased differentiation into S100β-positive astrocytes (+23%). These effects were dependent on the mineralocorticoid receptor (MR) as they were abolished by the MR antagonist, spironolactone, and mimicked by the MR-agonist, aldosterone. In contrast, high concentrations of cortisol (100 μM) decreased proliferation (-17%) and neuronal differentiation into MAP2-positive neurons (-22%) and into Dcx-positive neuroblasts (-27%), without regulating astrogliogenesis. These effects were dependent on the glucocorticoid receptor (GR), blocked by the GR antagonist RU486, and mimicked by the GR-agonist, dexamethasone. Gene expression microarray and pathway analysis showed that the low concentration of cortisol enhances Notch/Hes-signaling, the high concentration inhibits TGFβ-SMAD2/3-signaling, and both concentrations inhibit Hedgehog signaling. Mechanistically, we show that reduced Hedgehog signaling indeed critically contributes to the cortisol-induced reduction in neuronal differentiation. Accordingly, TGFβ-SMAD2/3 and Hedgehog signaling were also inhibited in the hippocampus of adult prenatally stressed rats with high glucocorticoid levels. In conclusion, our data demonstrate novel molecular signaling pathways that are regulated by glucocorticoids in vitro, in human hippocampal progenitor cells, and by stress in vivo, in the rat hippocampus.

Doublecortin is a neuronal microtubule-associated protein that regulates microtubule structure in neurons. Mutations in Doublecortin cause lissencephaly and subcortical band heterotopia by impairing neuronal migration. We use CRISPR/Cas9 to knock-out the Doublecortin gene in induced pluripotent stem cells and differentiate the cells into cortical neurons. DCX-KO neurons show reduced velocities of nuclear movements and an increased number of neurites early in neuronal development, consistent with previous findings. Neurite branching is regulated by a host of microtubule-associated proteins, as well as by microtubule polymerization dynamics. However, EB comet dynamics are unchanged in DCX-KO neurons. Rather, we observe a significant reduction in α-tubulin polyglutamylation in DCX-KO neurons. Polyglutamylation levels and neuronal branching are rescued by expression of Doublecortin or of TTLL11, an α-tubulin glutamylase. Using U2OS cells as an orthogonal model system, we show that DCX and TTLL11 act synergistically to promote polyglutamylation. We propose that Doublecortin acts as a positive regulator of α-tubulin polyglutamylation and restricts neurite branching. Our results indicate an unexpected role for Doublecortin in the homeostasis of the tubulin code. Lissencephaly is a severe neurodevelopmental disease often caused by mutations in the Dcx gene. Using a human cellular model of lissencephaly, the authors report that DCX restricts neuronal branching by activating tubulin polyglutamylation.