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Wnt5a Regulates Ventral Midbrain Morphogenesis and the Development of A9–A10 Dopaminergic Cells In Vivo  [PDF]
Emma R. Andersson, Nilima Prakash, Lukas Cajanek, Eleonora Minina, Vitezslav Bryja, Lenka Bryjova, Terry P. Yamaguchi, Anita C. Hall, Wolfgang Wurst, Ernest Arenas
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0003517
Abstract: Wnt5a is a morphogen that activates the Wnt/planar cell polarity (PCP) pathway and serves multiple functions during development. PCP signaling controls the orientation of cells within an epithelial plane as well as convergent extension (CE) movements. Wnt5a was previously reported to promote differentiation of A9–10 dopaminergic (DA) precursors in vitro. However, the signaling mechanism in DA cells and the function of Wnt5a during midbrain development in vivo remains unclear. We hereby report that Wnt5a activated the GTPase Rac1 in DA cells and that Rac1 inhibitors blocked the Wnt5a-induced DA neuron differentiation of ventral midbrain (VM) precursor cultures, linking Wnt5a-induced differentiation with a known effector of Wnt/PCP signaling. In vivo, Wnt5a was expressed throughout the VM at embryonic day (E)9.5, and was restricted to the VM floor and basal plate by E11.5–E13.5. Analysis of Wnt5a?/? mice revealed a transient increase in progenitor proliferation at E11.5, and a precociously induced NR4A2+ (Nurr1) precursor pool at E12.5. The excess NR4A2+ precursors remained undifferentiated until E14.5, when a transient 25% increase in DA neurons was detected. Wnt5a?/? mice also displayed a defect in (mid)brain morphogenesis, including an impairment in midbrain elongation and a rounded ventricular cavity. Interestingly, these alterations affected mostly cells in the DA lineage. The ventral Sonic hedgehog-expressing domain was broadened and flattened, a typical CE phenotype, and the domains occupied by Ngn2+ DA progenitors, NR4A2+ DA precursors and TH+ DA neurons were rostrocaudally reduced and laterally expanded. In summary, we hereby describe a Wnt5a regulation of Wnt/PCP signaling in the DA lineage and provide evidence for multiple functions of Wnt5a in the VM in vivo, including the regulation of VM morphogenesis, DA progenitor cell division, and differentiation of NR4A2+ DA precursors.
Wnt5a Regulates Midbrain Dopaminergic Axon Growth and Guidance  [PDF]
Brette D. Blakely,Christopher R. Bye,Chathurini V. Fernando,Malcolm K. Horne,Maria L. Macheda,Steven A. Stacker,Ernest Arenas,Clare L. Parish
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0018373
Abstract: During development, precise temporal and spatial gradients are responsible for guiding axons to their appropriate targets. Within the developing ventral midbrain (VM) the cues that guide dopaminergic (DA) axons to their forebrain targets remain to be fully elucidated. Wnts are morphogens that have been identified as axon guidance molecules. Several Wnts are expressed in the VM where they regulate the birth of DA neurons. Here, we describe that a precise temporo-spatial expression of Wnt5a accompanies the development of nigrostriatal projections by VM DA neurons. In mice at E11.5, Wnt5a is expressed in the VM where it was found to promote DA neurite and axonal growth in VM primary cultures. By E14.5, when DA axons are approaching their striatal target, Wnt5a causes DA neurite retraction in primary cultures. Co-culture of VM explants with Wnt5a-overexpressing cell aggregates revealed that Wnt5a is capable of repelling DA neurites. Antagonism experiments revealed that the effects of Wnt5a are mediated by the Frizzled receptors and by the small GTPase, Rac1 (a component of the non-canonical Wnt planar cell polarity pathway). Moreover, the effects were specific as they could be blocked by Wnt5a antibody, sFRPs and RYK-Fc. The importance of Wnt5a in DA axon morphogenesis was further verified in Wnt5a?/? mice, where fasciculation of the medial forebrain bundle (MFB) as well as the density of DA neurites in the MFB and striatal terminals were disrupted. Thus, our results identify a novel role of Wnt5a in DA axon growth and guidance.
Sonic Hedgehog Is a Chemoattractant for Midbrain Dopaminergic Axons  [PDF]
Rachel Hammond, Sandra Blaess, Asa Abeliovich
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0007007
Abstract: Midbrain dopaminergic axons project from the substantia nigra (SN) and the ventral tegmental area (VTA) to rostral target tissues, including the striatum, pallidum, and hypothalamus. The axons from the medially located VTA project primarily to more medial target tissues in the forebrain, whereas the more lateral SN axons project to lateral targets including the dorsolateral striatum. This structural diversity underlies the distinct functions of these pathways. Although a number of guidance cues have been implicated in the formation of the distinct axonal projections of the SN and VTA, the molecular basis of their diversity remains unclear. Here we investigate the molecular basis of structural diversity in mDN axonal projections. We find that Sonic Hedgehog (Shh) is expressed at a choice point in the course of the rostral dopaminergic projections. Furthermore, in midbrain explants, dopaminergic projections are attracted to a Shh source. Finally, in mice in which Shh signaling is inactivated during late neuronal development, the most medial dopaminergic projections are deficient. In addition to the role of Shh in the induction of mDN precursors, Shh plays an important role in dopaminergic axon pathfinding to rostral target tissues. Furthermore, Shh signaling is involved in determining the structural diversity of these dopaminergic projections.
Temporal-spatial changes in Sonic Hedgehog expression and signaling reveal different potentials of ventral mesencephalic progenitors to populate distinct ventral midbrain nuclei
Sandra Blaess, Gabriela O Bodea, Anna Kabanova, Soline Chanet, Emilie Mugniery, Amin Derouiche, Daniel Stephen, Alexandra L Joyner
Neural Development , 2011, DOI: 10.1186/1749-8104-6-29
Abstract: We employed genetic inducible fate mapping (GIFM) to investigate whether precursors that express Shh (Shh-GIFM) or transduce Shh signaling (Gli1-GIFM) at different time points give rise to different ventral midbrain cell types. We find that precursors restricted to the ventral midline are labeled at embryonic day (E)7.5 with Gli1-GIFM, and with Shh-GIFM at E8.5. These precursors give rise to all subtypes of midbrain dopaminergic neurons and the anterior RN. A broader domain of progenitors that includes the ventral midline is marked with Gli1-GIFM at E8.5 and with Shh-GIFM at E9.5; these fate-mapped cells also contribute to all midbrain dopaminergic subtypes and to the entire RN. In contrast, a lateral progenitor domain that is labeled with Gli1-GIFM at E9.5 and with Shh-GIFM at E11.5 has a markedly reduced potential to give rise to the RN and to SN dopaminergic neurons, and preferentially gives rise to the ventral-medial VTA. In addition, cells derived from Shh- and Gli1-expressing progenitors located outside of the ventral midline give rise to astrocytes.We define a ventral midbrain precursor map based on the timing of Gli1 and Shh expression, and suggest that the diversity of midbrain dopaminergic neurons is at least partially determined during their precursor stage when their medial-lateral position, differential gene expression and the time when they leave the ventricular zone influence their fate decisions.The ventral mesencephalic progenitor domain generates a diverse array of distinct neuronal cell types, including neurons of the red nucleus (RN), motoneurons of the oculomotor nucleus and midbrain dopaminergic (DA) neurons. DA neurons are further organized into anatomically and functionally distinct subclasses [1]. The substantia nigra (SN), located in the lateral-ventral midbrain, projects to the dorsal-lateral striatum and is involved in the regulation of motor behaviors. The ventral tegmental area (VTA), located more medially, projects to corticolimbic tar
Midbrain dopaminergic neuron fate specification: Of mice and embryonic stem cells
Emily Gale, Meng Li
Molecular Brain , 2008, DOI: 10.1186/1756-6606-1-8
Abstract: Dopamine containing neurons are present in different positions in the vertebrate central nervous system with the largest assembly in the midbrain. Midbrain dopaminergic (mDA) neurons are separated into functionally distinct subgroups called the substantia nigra compacta (SNc (also called the A9 group) and the ventral tegmental area (VTA (also called the A10 group) based on their position within the midbrain and the target structures which they innervate [1]. Dopaminergic neurons of the SNc primarily project to the dorsolateral striatum and regulate motor function. The VTA neurons, on the other hand, project to the ventromedial striatum, cortical areas and the limbic system and are involved in emotional behaviour and mechanisms of natural motivation and reward. In humans, the preferential degeneration of SNc neurons results in Parkinson's disease whilst defects of the VTA neuron system are implicated in psychiatric disorders.Because of their involvement in Parkinson's disease and other mental disorders, mDA neurons have been a focus of clinical interest and a subject of intensive studies for a long time. For Parkinson's disease, a potential therapy is to replace the lost mDA neurons with healthy DA neurons that have been generated in vitro through the differentiation of stem cells. To achieve this, a comprehensive understanding of the genetic cues and extrinsic signalling cascade controlling the fate choice of pluripotent embryonic stem (ES) cells into neuroepithelial stem cells and subsequently into functional midbrain specific DA neurons is required. In this regard, recent studies have identified a number of regulatory factors that influence the emergence of mDA neurons during vertebrate embryogenesis. These studies not only have increased our understanding of mDA neuron development in vivo, they have also guided the development of new paradigms for the in vitro generation of mDA neurons from ES cells. In return, ES cell differentiation in vitro provides a powerful
En1 and Wnt signaling in midbrain dopaminergic neuronal development
Maria TM Alves dos Santos, Marten P Smidt
Neural Development , 2011, DOI: 10.1186/1749-8104-6-23
Abstract: The mesodiencephalic dopaminergic (mdDA) system has been the focus of intense scientific research due to its involvement in numerous behavioral and neurological disorders and thus its clinical relevance. The neurotransmitter dopamine (DA) is present in different areas of the brain, such as the hypothalamus, the olfactory bulb and the mid-forebrain. In this last area, mdDA neurons are the main source of dopamine in the mammalian central nervous system (CNS), attributable to two ventral groups of neurons: the substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA) [1-3]. The main innervation targets of mdDA neurons are the basal ganglia. The neurons of the SNc innervate the dorsolateral striatum and caudate putamen forming the nigrostriatal pathway. Neurons of the VTA project to the ventral striatum (nucleus accumbens, amygdala and olfactory tubercle) as part of the mesolimbic system and establish additional ascending connections to the prefrontal cortex forming the mesocortical system. These ventral midbrain nuclei modulate specific brain functions according to its distinct projection fields. The SNc is involved in the control of voluntary movement and body posture, and its selective degeneration leads to Parkinson's disease (PD) [4,5]. The mesocortical and mesolimbic systems, on the other hand, are involved in the modulation and control of cognitive and emotional/rewarding behaviors, and their dysfunction is involved in the pathogenesis of various affective disorders, such as addiction [6-8], depression [9] and schizophrenia [10,11]. Drug abuse, depression and PD constitute highly common health disorders, which explains the intense research in recent years on the mechanisms and factors involved in the generation and survival of mammalian mdDA neurons.The development of an organ, such as the midbrain, implies the sequential occurrence of developmental cascades over time, while these might overlap in time and space [12-14]. During early neuronal indu
INTERACTION OF VESICULAR MONOAMINE TRANSPORTER 2 (VMAT2) AND NEUROMELANIN PIGMENT AMONG THE MIDBRAIN DOPAMINERGIC NEURONS, IN MAN
P. Pasbakhsh,D.C. German N. Omidi
Acta Medica Iranica , 2004,
Abstract: Neuromelanin (NM) pigment accumulates with age in catecholaminergic neurons in man, and the ventral substantia nigra dopaminergic neurons that are the most vulnerable to degeneration in Parkinson's disease (PD) contain the greatest amount of this pigment. In vitro data indicate that NM pigment is formed from the excess cytosolic catecholamine that is not accumulated into synaptic vesicles via the vesicular monoamine transporter2 (VMAT2). Using semi-quantitative immunohistochemical methods in human postmortem brain, we sought to examine the relationship between the contents of VMAT2 and NM pigment. The immunostaining intensity (ISI) was measured for VMAT2 in two regions of the midbrain dopaminergic cell complex. The ISI of the cells was related to the density of NM pigment within the cells. We also measured the ISI for tyrosine hydroxylase (TH) and examined the noradrenergic neurons in the locus coeruleus (LC). In brains 22-65 years of age: 1) ventral substantia nigra neurons had the lowest VMAT2 ISI of all neurons in the midbrain cell complex, whereas over 2-fold higher levels are found in most ventral tegmental area neurons; 2) there was an inverse relationship between VMAT2 ISI and neuromelanin pigment in the midbrain dompaminergic neurons; 3) neurons with the highest VMAT2 ISI resided in the LC; 4) neurons with high VMAT2 ISI also had high TH ISI; and 5) in the newborn brain, which has not yet accumulated neuromelanin pigment in the aminergic neurons, the regional distribution of VMAT2 and TH-ISI was similar to that found in the adult brain. These data support the hypothesis that among the midbrain dopaminergic neurons, the ventral substantia nigra dopamine neurons accumulate the highest levels of NM pigment because they have the lowest levels of VMAT2, which thereby renders them especially vulnerable to degeneration in PD.
Disrupted Functional Connectivity with Dopaminergic Midbrain in Cocaine Abusers  [PDF]
Dardo Tomasi,Nora D. Volkow,Ruiliang Wang,Jean H. Carrillo,Thomas Maloney,Nelly Alia-Klein,Patricia A. Woicik,Frank Telang,Rita Z. Goldstein
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0010815
Abstract: Chronic cocaine use is associated with disrupted dopaminergic neurotransmission but how this disruption affects overall brain function (other than reward/motivation) is yet to be fully investigated. Here we test the hypothesis that cocaine addicted subjects will have disrupted functional connectivity between the midbrain (where dopamine neurons are located) and cortical and subcortical brain regions during the performance of a sustained attention task.
Stimulation of Midbrain Dopaminergic Structures Modifies Firing Rates of Rat Lateral Habenula Neurons  [PDF]
Xuefeng Shen, Xiaoguo Ruan, Hua Zhao
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0034323
Abstract: Ventral tegmental area (VTA) and substantia nigra pars compacta (SNpc) are midbrain structures known to be involved in mediating reward in rodents. Lateral habenula (LHb) is considered as a negative reward source and it is reported that stimulation of the LHb rapidly induces inhibition of firing in midbrain dopamine neurons. Interestingly, the phasic fall in LHb neuronal activity may follow the excitation of dopamine neurons in response to reward-predicting stimuli. The VTA and SNpc give rise to dopaminergic projections that innervate the LHb, which is also known to be involved in processing painful stimuli. But it's unclear what physiological effects these inputs have on habenular function. In this study we distinguished the LHb pain-activated neurons of the Wistar rats and assessed their electrophysiological responsiveness to the stimulation of the VTA and SNpc with either single-pulse stimulation (300 μA, 0.5 Hz) or tetanic stimulation (80 μA, 25 Hz). Single-pulse stimulation that was delivered to either midbrain structure triggered transient inhibition of firing of ~90% of the LHb pain-activated neurons. However, tetanic stimulation of the VTA tended to evoke an elevation in neuronal firing rate. We conclude that LHb pain-activated neurons can receive diverse reward-related signals originating from midbrain dopaminergic structures, and thus participate in the regulation of the brain reward system via both positive and negative feedback mechanisms.
Calcitriol Imparts Neuroprotection In Vitro to Midbrain Dopaminergic Neurons by Upregulating GDNF Expression  [PDF]
Rowan P. Orme, Manminder S. Bhangal, Rosemary A. Fricker
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0062040
Abstract: During development a tightly controlled signaling cascade dictates the differentiation, maturation and survival of developing neurons. Understanding this signaling mechanism is important for developing therapies for neurodegenerative illnesses. In previous work we have sought to understand the complex signaling pathways responsible for the development of midbrain dopamine neurons using a proteomic approach. One protein we have identified as being expressed in developing midbrain tissue is the vitamin D receptor. Therefore we investigated the effect of the biologically active vitamin D3 metabolite, calcitriol, on primary fetal ventral mesencephalic cultures of dopamine neurons. We observed a dose responsive increase in numbers of rat primary dopamine neurons when calcitriol was added to culture media. Western blot data showed that calcitriol upregulated the expression of glial derived neurotrophic factor (GDNF). Blocking GDNF signaling could prevent calcitriol’s ability to increase numbers of dopamine neurons. An apoptosis assay and cell birth dating experiment revealed that calcitriol increases the number of dopamine neurons through neuroprotection and not increased differentiation. This could have implications for future neuroprotective PD therapies.
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