Migration Of Precursors Research Articles

Detection of mouse endogenous type B astrocytes migrating towards brain lesions

Neuroblasts represent the predominant migrating cell type in the adult mouse brain. There are, however, increasing evidences of migration of other neural precursors. This work aims at identifying in vivo endogenous early neural precursors, different from neuroblasts, able to migrate in response to brain injuries. The monoclonal antibody Nilo1, which unequivocally identifies type B astrocytes and embryonic radial glia, was coupled to magnetic glyconanoparticles (mGNPs). Here we show that Nilo1–mGNPs in combination with magnetic resonance imaging in living mice allowed the in vivo identification of endogenous type B astrocytes at their niche, as well as their migration to the lesion site in response to glioblastoma, demyelination, cryolesion or mechanical injuries. In addition, Nilo1+ adult radial glia-like structures were identified at the lesion site a few hours after damage. For all damage models used, type B astrocyte migration was fast and orderly. Identification of Nilo1+ cells surrounding an induced glioblastoma was also possible after intraperitoneal injection of the antibody. This opens up the possibility of an early identification of the initial damage site(s) after brain insults, by the migration of type B astrocytes.

Promotion of periostin expression contributes to the migration of Schwann cells.

Neuregulin ligands and their ErbB receptors are important for the development of Schwann cells, the glial cells of the peripheral nervous system (PNS). ErbB3 deficiency is characterized by a complete loss of Schwann cells along axons of the peripheral nerves, impaired fasciculation and neuronal cell death. We performed comparative gene expression analysis of dorsal root ganglia (DRG) explant cultures from ErbB3-deficient and wild-type mice in order to identify genes that are involved in Schwann cell development and migration. The extracellular matrix (ECM) gene periostin was found to exhibit the most prominent down regulation in ErbB3-deficient DRG. Expression analysis revealed that the periostin-expressing cell population in the PNS corresponds to Schwann cell precursors and Schwann cells, and is particularly high in migratory Schwann cells. Furthermore, stimulation of Schwann cells with neuregulin-1 (NRG1) or transforming growth factor β (TGFβ-1) resulted in an upregulation of periostin expression. Interestingly, DRG explant cultures of periostin-deficient mice revealed a significant reduction of the number of migrating Schwann cells. These data demonstrate that the expression of periostin is stimulated by ErbB ligand NRG1 and influences the migration of Schwann cell precursors.

Chapter 7 - Neurocutaneous melanosis

Neurocutaneous melanosis is a rare neurocutaneous syndrome that is associated with a high rate of mortality early in life. Individuals with large cutaneous melanocytic nevi (LCMN) are at risk, especially when the nevi are posterior, midline and accompanied by satellite nevi. Disrupted production and migration of melanocytic precursors from neural crest likely are responsible. Although the cutaneous lesions are at risk for melanoma, the most likely source of morbidity and mortality comes from "benign" melanocytic proliferation in the brain or central nervous system melanoma. Seizures and hydrocephalus are the common neurologic manifestations and typically arise in the first years of life. Brain magnetic resonance imaging in infants before myelination has matured is most sensitive for detecting abnormal melanosis in the brain, which preferentially involves the leptomeninges, cerebellum and anterior temporal lobes. Treatment is symptomatic and death occurs in many within 3 years of onset of neurologic symptoms. This prognosis may limit the extent to which extensive procedures or interventions are undertaken.

Cross-species epigenetics identifies a critical role for VAV1 in SHH subgroup medulloblastoma maintenance.

The identification of key tumorigenic events in Sonic Hedgehog subgroup medulloblastomas (MBSHH) will be essential for the development of individualized therapies and improved outcomes. However, beyond confirmation of characteristic SHH-pathway mutations, recent genome-wide sequencing studies have not revealed commonly-mutated genes with widespread relevance as potential therapeutic targets. We therefore examined any role for epigenetic DNA methylation events in MBSHH using a cross-species approach to candidate identification, prioritization and validation. MBSHH–associated DNA methylation events were first identified in 216 subgrouped human medulloblastomas (50 MBSHH, 28 WNT, 44 Group 3, 94 Group 4) and their conservation then assessed in tumors arising from four independent murine models of Shh medulloblastoma, alongside any role in tumorigenesis using functional assessments in mouse and human models. This strategy identified widespread regional CpG hypo-methylation of VAV1, leading to its elevated expression, as a conserved aberrant epigenetic event which characterizes the majority of MBSHH tumors in both species, and is associated with a poor outcome in MBSHH patients. Moreover, direct modulation of VAV1 in mouse and human models revealed a critical role in tumor maintenance, and its abrogation markedly reduced medulloblastoma growth. Further, Vav1 activity regulated granule neuron precursor (GNP) germinal zone exit and migration initiation in an ex vivo model of early post-natal cerebellar development. These findings establish VAV1 as a critical epigenetically-regulated oncogene with a key role in MBSHH maintenance, and highlight its potential as a validated therapeutic target and prognostic biomarker for the improved therapy of medulloblastoma.

Propane Dehydrogenation over Pt/TiO2–Al2O3 Catalysts

This paper describes an investigation on understanding catalytic consequences of Pt nanoparticles supported on a TiO2–Al2O3 binary oxide for propane dehydrogenation (PDH). The TiO2–Al2O3 supports were synthesized by a sol–gel method, and the Pt/TiO2–Al2O3 catalysts were prepared by an incipient wetness impregnation method. Both as-prepared and post-experiment catalysts were characterized employing N2 adsorption–desorption, X-ray diffraction, Raman spectra, H2–O2 titration, temperature-programmed desorption, thermogravimetric analysis, temperature-programmed oxidation, transmission electron microscopy, and Fourier-transform infrared spectra of chemisorbed CO. We have shown that TiO2 is highly dispersed on Al2O3, and the addition of appropriate amount of TiO2 improves propylene selectivity and catalytic stability, which is ascribed to the electron transfer from partially reduced TiOx (x < 2) to Pt atoms. The increased electron density of Pt could reduce the adsorption of propylene and facilitate the migration of coke precursors from the metal surface to the support. The addition of TiO2, however, also increases the amount of strong acid centers on the supports and the excessive TiO2 addition might lead to a significant amount of coke formation. The electron transfer effect and the acid sites effect of TiO2 addition exert an opposite influence on catalytic performance. The trade-off between the electron transfer effect and the acid sites effect is studied by varying the amount of TiO2 loading. An optimal loading content of TiO2 is 10 wt %, which results in a higher propylene selectivity and a better stability.

GABAρ subunits confer a bicuculline-insensitive component to GFAP+ cells of cerebellum.

GABA-A receptors mediating synaptic or extrasynaptic transmission are molecularly and functionally distinct, and glial cells are known to express a plethora of GABA-A subunits. Here we demonstrate that GFAP(+) cells of the granular layer of cerebellum express GABAρ subunits during early postnatal development, thereby conferring peculiar pharmacologic characteristics to GABA responses. Electron microscopy revealed the presence of GABAρ in the plasma membrane of GFAP(+) cells. In contrast, expression in the adult was restricted to Purkinje neurons and a subset of ependymal cells. Electrophysiological studies in vitro revealed that astrocytes express functional receptors with an EC50 of 52.2 ± 11.8 μM for GABA. The evoked currents were inhibited by bicuculline (100 μM) and TPMPA (IC50, 5.9 ± 0.6 μM), indicating the presence of a GABAρ component. Coimmunoprecipitation demonstrated protein-protein interactions between GABAρ1 and GABAα1, and double immunofluorescence showed that these subunits colocalize in the plasma membrane. Three populations of GABA-A receptors in astrocytes were identified: classic GABA-A, bicuculline-insensitive GABAρ, and GABA-A-GABAρ hybrids. Clusters of GABA-A receptors were distributed in the perinuclear space and along the processes of GFAP(+) cells. Time-lapse microscopy showed GABAρ2-GFP accumulation in clusters located in the soma and along the processes. The clusters were relatively immobile, with mean displacement of 9.4 ± 0.9 μm and a net distance traveled of 1-2 μm, owing mainly to directional movement or simple diffusion. Modulation of GABAρ dynamics may be a novel mechanism of extrasynaptic transmission regulating GABAergic control of GFAP(+) cells during early postnatal development.

Epigenetic control of Ccr7 expression in distinct lineages of lung dendritic cells.

Adaptive immune responses to inhaled allergens are induced following CCR7-dependent migration of precursor of dendritic cell (pre-DC)-derived conventional DCs (cDCs) from the lung to regional lymph nodes. However, monocyte-derived (moDCs) in the lung express very low levels of Ccr7 and consequently do not migrate efficiently to LN. To investigate the molecular mechanisms that underlie this dichotomy, we studied epigenetic modifications at the Ccr7 locus of murine cDCs and moDCs. When expanded from bone marrow precursors, moDCs were enriched at the Ccr7 locus for trimethylation of histone 3 lysine 27 (H3K27me3), a modification associated with transcriptional repression. Similarly, moDCs prepared from the lung also displayed increased levels of H3K27me3 at the Ccr7 promoter compared with migratory cDCs from that organ. Analysis of DC progenitors revealed that epigenetic modification of Ccr7 does not occur early during DC lineage commitment because monocytes and pre-DCs both had low levels of Ccr7-associated H3K27me3. Rather, Ccr7 is gradually silenced during the differentiation of monocytes to moDCs. Thus, epigenetic modifications of the Ccr7 locus control the migration and therefore the function of DCs in vivo. These findings suggest that manipulating epigenetic mechanisms might be a novel approach to control DC migration and thereby improve DC-based vaccines and treat inflammatory diseases of the lung.

Critical role of Spns2, a sphingosine-1-phosphate transporter, in lung cancer cell survival and migration.

The sphingosine-1-phosphate (S1P) transporter Spns2 regulates myocardial precursor migration in zebrafish and lymphocyte trafficking in mice. However, its function in cancer has not been investigated. We show here that ectopic Spns2 expression induced apoptosis and its knockdown enhanced cell migration in non-small cell lung cancer (NSCLC) cells. Metabolically, Spns2 expression increased the extracellular S1P level while its knockdown the intracellular. Pharmacological inhibition of S1P synthesis abolished the augmented cell migration mediated by Spns2 knockdown, indicating that intracellular S1P plays a key role in this process. Cell signaling studies indicated that Spns2 expression impaired GSK-3β and Stat3 mediated pro-survival pathways. Conversely, these pathways were activated by Spns2 knockdown, which explains the increased cell migration since they are also crucial for migration. Alterations of Spns2 were found to affect several enzymes involved in S1P metabolism, including sphingosine kinases, S1P phosphatases, and S1P lyase 1. Genetically, Spns2 mRNA level was found to be reduced in advanced lung cancer (LC) patients as quantified by using a small scale qPCR array. These data show for the first time that Spns2 plays key roles in regulating the cellular functions in NSCLC cells, and that its down-regulation is a potential risk factor for LC.

Astrocytic and vascular scaffolding for neuroblast migration in the rostral migratory stream.

New neurons are continuously being added to the olfactory bulb (OB) of adult rodents that are generated in the subventricular zone (SVZ), distant by a few millimeters. Neuronal precursors have to overcome this long distance without the radial-glial migratory scaffold, in contrast to migration mode during embryonic development. The previous model explains migration of precursors from the SVZ through the rostral migratory stream (RMS) to the OB as a movement of neuroblasts along each other, ensheathed by astroglial tubes. Recent results indicate that blood vessels are suitable candidates for neuronal migration guidance in the RMS. These novel findings have changed the former concept accounting for neuronal precursor migration. The aim of our study was to map a pattern of vascularization in the RMS of adult rats and to investigate mutual relations among blood vessels, neuroblasts and astrocytes in this area. Detailed morphological analysis revealed that blood vessels in the RMS are organized in a specific manner. In most of the RMS extent, blood vessels run parallel to the outline of the migratory pathway. Interestingly, the caudal part of the RMS has a unique vasculature organization in which blood vessels create a spiral-like configuration. Chains of neuroblasts enveloped by astrocytes largely align along blood vessels. The exception is the caudal part of the RMS where neuroblasts do not follow non - parallel blood vessels. Our morphological findings suggest that blood vessels and astrocytes may cooperatively form physical substrate - scaffold for the neuroblasts migration in the RMS of adult rats.

Primary Gastric Melanoma: Wait, I Thought the Stomach Did Not Have Any Melanocytes!

Introduction: We report a case of a patient who presented with abdominal pain and decreased ability to tolerate food, and was found to have melanoma in the gastric mucosa. We highlight the difficulty of diagnosing primary gastric melanoma with certainty, given its rarity and theoretical implausibility, as normal gastric epithelium lacks melanocytes. We also briefly review several pathophysiologic and embryologic hypotheses for this phenomenon. A 50-year-old Hispanic male presented to our clinic with epigastric pain and decreased ability to tolerate food. An EGD revealed a large, irregular ulcerated gastric mass extending 1.5 to 2 cm from the gastroesophageal junction to the antrum. The mass was biopsied, and immunohistochemical stains showed the tumor cells were positive for melan-A, HMB45 and vimentin, confirming melanoma. A thorough search for another possible primary lesion, consisting of a complete skin examination and positron emission tomography (PET), did not identify a clear primary site of melanoma. The PET scan revealed uptake involving the gastric walls and lymph nodes in the perigastric, retroperitoneal and left supraclavicular regions. BRAF analysis was positive for a V600 mutation. The patient subsequently underwent palliative jejunostomy placement and was evaluated by medical oncology. Primary gastric melanoma is extremely rare (with only a handful of cases reported in the literature), likely due to the lack of melanocytes in normal gastric epithelium. Therefore, when melanoma is encountered in the stomach, it is crucial to search for a primary melanocytic lesion that may have metastasized to the stomach. While gastrointestinal involvement by melanoma has been found in up to 60% of autopsies of patients who have died with primary cutaneous melanoma, melanoma located primarily in the gastric mucosa is an uncommon occurrence. Several pathophysiologic mechanisms have been suggested. Ectopic migration of melanocyte precursors or differentiation of the APUD cells to melanocytes have been suggested as possible mechanisms. Spontaneous regression of primary melanoma has also been recognized, and it is possible that our patient’s gastric melanoma may have represented a metastasis from primary lesion that had spontaneously regressed. The median overall survival for primary melanoma of the GI tract is 17 months; for primary melanoma of the stomach, 5 months. There is little consensus on therapy for patients with primary GI melanoma, but treatment with complete excision may provide long-term disease-free survival. Vemurafenib, a BRAF kinase inhibitor, has been shown to improve both overall and progression-free survival in patients with metastatic melanoma with the BRAF V600E mutation

Long-distance cell migration during larval development in the appendicularian, Oikopleura dioica

The appendicularian, Oikopleura dioica, is a planktonic chordate. Its simple and transparent body, invariant cell lineages and short life cycle of 5 days make it a promising model organism for studies of chordate development. Here we describe the cell migration that occurs during development of the O. dioica larva. Using time-lapse imaging facilitated by florescent labeling of cells, three cell populations exhibiting long-distance migration were identified and characterized. These included (i) a multinucleated oral gland precursor that migrates anteriorly within the trunk region and eventually separates into the left and right sides, (ii) endodermal strand cells that are collectively retracted from the tail into the trunk in a tractor movement, and (iii) two subchordal cell precursors that individually migrate out from the trunk to the tip of the tail. The migration of subchordal cell precursors starts when all of the endodermal strand cells enter the trunk, and follows the same path but in a direction opposite to that of the latter. Labeling of these cells with a photoconvertible fluorescent protein, Kaede, demonstrated that the endodermal strand cells and subchordal cell precursors have distinct origins and eventual fates. Surgical removal of the trunk from the tail demonstrated that the endodermal strand cells do not require the trunk for migration, and that the subchordal cell precursors would be attracted by the distal part of the tail. This well-defined, invariant and traceable long-distance cell migration provides a unique experimental system for exploring the mechanisms of versatile cell migration in this simple organism with a chordate body plan.

In vivo knockdown of ErbB3 in mice inhibits Schwann cell precursor migration

The myelin sheath insulates neuronal axons and markedly increases the nerve conduction velocity. In the peripheral nervous system (PNS), Schwann cell precursors migrate along embryonic neuronal axons to their final destinations, where they eventually wrap around individual axons to form the myelin sheath after birth. ErbB2 and ErbB3 tyrosine kinase receptors form a heterodimer and are extensively expressed in Schwann lineage cells. ErbB2/3 is thought to be one of the primary regulators controlling the entire Schwann cell development. ErbB3 is the bona fide Schwann cell receptor for the neuronal ligand neuregulin-1. Although ErbB2/3 is well known to regulate both Schwann cell precursor migration and myelination by Schwann cells in fishes, it still remains unclear whether in mammals, ErbB2/3 actually regulates Schwann cell precursor migration. Here, we show that knockdown of ErbB3 using a Schwann cell-specific promoter in mice causes delayed migration of Schwann cell precursors. In contrast, littermate control mice display normal migration. Similar results are seen in an in vitro migration assay using reaggregated Schwann cell precursors. Also, ErbB3 knockdown in mice reduces myelin thickness in sciatic nerves, consistent with the established role of ErbB3 in myelination. Thus, ErbB3 plays a key role in migration, as well as in myelination, in mouse Schwann lineage cells, presenting a genetically conservative role of ErbB3 in Schwann cell precursor migration.

Effect of Hydrogen Neutral Beam on the Growth of Nanocrystalline Silicon

We have investigated the effect of hydrogen neutral beam(H-NB) on the nano-crystalline silicon (nc-Si) thin films using the neutral beam assisted chemical vapor deposition (NBaCVD) system. In traditional hydrogenated silicon deposition, the gas mixture ratio of hydrogen and silane (SiH4) controls the phase of the thin films, including that from hydrogenated amorphous silicon (a-Si:H) to microcrystalline silicon (μc-Si). However, poor migration of deposition precursor and the absence of nucleation sites cause silicon background to be amorphous in the early stage of growth. Conversely, The NBaCVD technology controls the energy of neutral particles (mainly hydrogen atoms) in the range of 0-300 eV to enhance the crystallinity during thin film deposition at low temperature (<80 °C). The growth mechanism of the nc-Si thin film by the NBaCVD process differs from that of the nc-Si by conventional PECVD. The nc-Si thin films crystal volume fraction increases rapidly and saturates near 80 % while the grain size becomes gradually larger in a range of 4~5.5 nm as the H-NB kinetic energy (reflector bias) increases. Because the nucleation and nc-grain growth should be initiated on the sub-layer surface due to assistance of the energetic H-NB particles, an incubation layer is eliminated effectively. The structural state was estimated by micro Raman spectroscopy. The microstructure was analyzed by field emission transmission electron microscopy (FE-TEM). Finally, the very low temperature processed nc-Si TFT show much improved stabilities against sever positive bias light stress (PBIS; Vg= 20 V, Vd= 1 V, 100 mW/cm2 Halogen Lamp) condition, while the field effect mobility was up to 3.2 cm2/Vs: threshold voltage shift was smaller than 1 V after 104sec under the PBIS conditions.

Differential requirement for CCR4 and CCR7 during the development of innate and adaptive αβT cells in the adult thymus.

αβT cell development depends upon serial migration of thymocyte precursors through cortical and medullary microenvironments, enabling specialized stromal cells to provide important signals at specific stages of their development. Although conventional αβT cells are subject to clonal deletion in the medulla, entry into the thymus medulla also fosters αβT cell differentiation. For example, during postnatal periods, the medulla is involved in the intrathymic generation of multiple αβT cell lineages, notably the induction of Foxp3+ regulatory T cell development and the completion of invariant NKT cell development. Although migration of conventional αβT cells to the medulla is mediated by the chemokine receptor CCR7, how other T cell subsets gain access to medullary areas during their normal development is not clear. In this study, we show that combining a panel of thymocyte maturation markers with cell surface analysis of CCR7 and CCR4 identifies distinct stages in the development of multiple αβT cell lineages in the thymus. Although Aire regulates expression of the CCR4 ligands CCL17 and CCL22, we show that CCR4 is dispensable for thymocyte migration and development in the adult thymus, demonstrating defective T cell development in Aire−/− mice is not because of a loss of CCR4-mediated migration. Moreover, we reveal that CCR7 controls the development of invariant NKT cells by enabling their access to IL-15 trans-presentation in the thymic medulla and influences the balance of early and late intrathymic stages of Foxp3+ regulatory T cell development. Collectively, our data identify novel roles for CCR7 during intrathymic T cell development, highlighting its importance in enabling multiple αβT cell lineages to access the thymic medulla.

Angiogenesis in multiple sclerosis and experimental autoimmune encephalomyelitis.

Angiogenesis, the formation of new vessels, is found in Multiple Sclerosis (MS) demyelinating lesions following Vascular Endothelial Growth Factor (VEGF) release and the production of several other angiogenic molecules. The increased energy demand of inflammatory cuffs and damaged neural cells explains the strong angiogenic response in plaques and surrounding white matter. An angiogenic response has also been documented in an experimental model of MS, experimental allergic encephalomyelitis (EAE), where blood–brain barrier disruption and vascular remodelling appeared in a pre-symptomatic disease phase. In both MS and EAE, VEGF acts as a pro-inflammatory factor in the early phase but its reduced responsivity in the late phase can disrupt neuroregenerative attempts, since VEGF naturally enhances neuron resistance to injury and regulates neural progenitor proliferation, migration, differentiation and oligodendrocyte precursor cell (OPC) survival and migration to demyelinated lesions. Angiogenesis, neurogenesis and oligodendroglia maturation are closely intertwined in the neurovascular niches of the subventricular zone, one of the preferential locations of inflammatory lesions in MS, and in all the other temporary vascular niches where the mutual fostering of angiogenesis and OPC maturation occurs. Angiogenesis, induced either by CNS inflammation or by hypoxic stimuli related to neurovascular uncoupling, appears to be ineffective in chronic MS due to a counterbalancing effect of vasoconstrictive mechanisms determined by the reduced axonal activity, astrocyte dysfunction, microglia secretion of free radical species and mitochondrial abnormalities. Thus, angiogenesis, that supplies several trophic factors, should be promoted in therapeutic neuroregeneration efforts to combat the progressive, degenerative phase of MS.

FGF/FGFR2 signaling regulates the generation and correct positioning of Bergmann glia cells in the developing mouse cerebellum.

The normal cellular organization and layering of the vertebrate cerebellum is established during embryonic and early postnatal development by the interplay of a complex array of genetic and signaling pathways. Disruption of these processes and of the proper layering of the cerebellum usually leads to ataxic behaviors. Here, we analyzed the relative contribution of Fibroblast growth factor receptor 2 (FGFR2)-mediated signaling to cerebellar development in conditional Fgfr2 single mutant mice. We show that during embryonic mouse development, Fgfr2 expression is higher in the anterior cerebellar primordium and excluded from the proliferative ventricular neuroepithelium. Consistent with this finding, conditional Fgfr2 single mutant mice display the most prominent defects in the anterior lobules of the adult cerebellum. In this context, FGFR2-mediated signaling is required for the proper generation of Bergmann glia cells and the correct positioning of these cells within the Purkinje cell layer, and for cell survival in the developing cerebellar primordium. Using cerebellar microexplant cultures treated with an FGFR agonist (FGF9) or antagonist (SU5402), we also show that FGF9/FGFR-mediated signaling inhibits the outward migration of radial glia and Bergmann glia precursors and cells, and might thus act as a positioning cue for these cells. Altogether, our findings reveal the specific functions of the FGFR2-mediated signaling pathway in the generation and positioning of Bergmann glia cells during cerebellar development in the mouse.

Retrograde migration of pectoral girdle muscle precursors depends on CXCR4/SDF-1 signaling.

In vertebrates, muscles of the pectoral girdle connect the forelimbs with the thorax. During development, the myogenic precursor cells migrate from the somites into the limb buds. Whereas most of the myogenic precursors remain in the limb bud to form the forelimb muscles, several cells migrate back toward the trunk to give rise to the superficial pectoral girdle muscles, such as the large pectoral muscle, the latissimus dorsi and the deltoid. Recently, this developing mode has been referred to as the "In-Out" mechanism. The present study focuses on the mechanisms of the "In-Out" migration during formation of the pectoral girdle muscles. Combining in ovo electroporation, tissue slice-cultures and confocal laser scanning microscopy, we visualize live in detail the retrograde migration of myogenic precursors from the forelimb bud into the trunk region by live imaging. Furthermore, we present for the first time evidence for the involvement of the chemokine receptor CXCR4 and its ligand SDF-1 during these processes. After microsurgical implantations of CXCR4 inhibitor beads in the proximal forelimb region of chicken embryos, we demonstrate with the aid of in situ hybridization and live-cell imaging that CXCR4/SDF-1 signaling is crucial for the retrograde migration of pectoral girdle muscle precursors. Moreover, we analyzed the MyoD expression in CXCR4-mutant mouse embryos and observed a considerable decrease in pectoral girdle musculature. We thus demonstrate the importance of the CXCR4/SDF-1 axis for the pectoral girdle muscle formation in avians and mammals.

Characterization of the nerve-stellate cell interactions in pancreatic cancer

Glial cell line-derived neurotrophic factor (GDNF) is expressed in the gastrointestinal tract of the developing mouse and appears to play an important role in the migration of enteric neuron precursors into and along the small and large intestines. Two other GDNF family members, neurturin and artemin, are also expressed in the developing gut although artemin is only expressed in the esophagus. We examined the effects of GDNF, neurturin, and artemin on neural crest cell migration and neurite outgrowth in explants of mouse esophagus, midgut, and hindgut. Both GDNF and neurturin induced neural crest cell migration and neurite outgrowth in all regions examined. In the esophagus, the effect of GDNF on migration and neurite outgrowth declined with age between E11.5 and E14.5, but neurturin still had a strong neurite outgrowth effect at E14.5. Artemin did not promote neural migration or neurite outgrowth in any region investigated. The effects of GDNF family ligands are mediated by the Ret tyrosine kinase. We examined the density of neurons in the esophagus of Ret−/− mice, which lack neurons in the small and large intestines. The density of esophageal neurons in Ret−/− mice was only about 4% of the density of esophageal neurons in Ret+/− and Ret+/+ mice. These results show that GDNF and neurturin promote migration and neurite outgrowth of crest-derived cells in the esophagus as well as the intestine. Moreover, like intestinal neurons, the development of esophageal neurons is largely Ret-dependent.

Role of periodontal ligament fibroblasts in osteoclastogenesis: a review.

During the last decade it has become clear that periodontal ligament fibroblasts may contribute to the in vitro differentiation of osteoclasts. We surveyed the current findings regarding their osteoclastogenesis potential. Periodontal ligament fibroblasts have the capacity to select and attract osteoclast precursors and subsequently to retract and enable migration of osteoclast precursors to the bone surface. There, fusion of precursors takes place, giving rise to osteoclasts. The RANKL-RANK-osteoprotegerin (OPG) axis is considered crucial in this process. Periodontal ligament fibroblasts produce primarily OPG, an osteoclastogenesis-inhibitory molecule. However, they may be influenced in vivo by direct or indirect interactions with bacteria or by mechanical loading. Incubation of periodontal ligament fibroblasts with bacteria or bacterial components causes an increased expression of RANKL and other osteoclastogenesis-stimulating molecules, such as tumor necrosis factor-α and macrophage-colony stimulating factor. Similar results are observed after the application of mechanical loading to these fibroblasts. Periodontal ligament fibroblasts may be considered to play an important role in the remodelling of alveolar bone. In vitro experiments have demonstrated that periodontal ligament fibroblasts adapt to bacterial and mechanical stimuli by synthesizing higher levels of osteoclastogenesis-stimulating molecules. Therefore, they probably contribute to the enhanced osteoclast formation observed during periodontitis and to orthodontic tooth movement.

The ventricular-subventricular zone: a source of oligodendrocytes in the adult brain.

The ventricular-subventricular zone: a source of oligodendrocytes in the adult brain.