St18 specifies globus pallidus projection neuron identity in MGE lineage

The medial ganglionic eminence (MGE) is a progenitor domain in the subpallium that produces both locally-projecting interneurons which undergo tangential migration in structures such as the cortex as well as long-range projection neurons that occupy subcortical nuclei. Very little is known about the transcriptional mechanisms specifying the migratory behavior and axonal projection patterns of these two broad classes of MGE-derived neurons. In this study, we identify St18 as a novel transcriptional determinant specifying projection neuron fate in the MGE lineage. St18 is transiently expressed in the MGE subventricular zone (SVZ) and mantle, and we assessed its function using an ES cell-based model of MGE development. Induction of St18 is sufficient to direct ES-derived MGE neurons to adopt a projection neuron-like identity as defined by migration and morphology. Using genetic loss-of-function in mice, we find that St18 is required for the production of globus pallidus pars externa (GPe) prototypic projection neurons. Single cell RNA sequencing revealed that St18 regulates MGE output of specific neuronal populations: in the absence of St18, we observe a large expansion of cortical interneurons at the expense of putative GPe neurons. Through gene expression analysis we identified a downstream effector of St18, Cbx7, which is a component of Polycomb repressor complex 1. We find that Cbx7 is essential for projection neuron-like migration and is not involved in St18-mediated projection neuron-like morphology. Our results characterize a novel transcriptional determinant that directs GPe prototypic projection neuron identity. Further, we identified a downstream target of St18, Cbx7, which regulates only the migratory behavior of long-range projection neurons, suggesting that specific features of MGE projection neuron identity may be governed in a compartmentalized fashion by distinct transcriptional modules downstream of St18.

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A novel subtype of pineal projection neurons expressing melanopsin share a common developmental program with classical projection neurons

10.1101/712091 ◽

2019 ◽

Author(s):

Dora Sapède ◽

Clair Chaigne ◽

Patrick Blader ◽

Elise Cau

Keyword(s):

Pineal Organ ◽

Hybrid Cell ◽

Projection Neuron ◽

Projection Neurons ◽

Cell Type ◽

Cell Fates ◽

Neuron Population ◽

Neuronal Populations ◽

Developmental Program

SummaryThe zebrafish pineal organ is a photoreceptive structure containing two main neuronal populations (photoreceptors and projections neurons). Here we describe a new pineal cell type that harbors both characteristics of projection neurons and photoreceptors. Indeed, a subpopulation of projection neurons expresses the melanopsin gene opn4xa suggesting photoreceptive properties. This population of hybrid cell fates, share a similar behaviour regarding dependency for BMP and Notch signalling pathways with classical non-photosensitive projection neurons (PNs) suggesting they are closer to the PN population. We describe two distinct types of activity within PNs: an achromatic LIGHT OFF activity in opn4xa− PNs and a LIGHT ON activity elicited by green and blue light in opn4xa+ PNs. Altogether the discovery and characterization of opn4xa+ PNs suggest a previously unanticipated heterogeneity in the projection neuron population.

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Area-specific development of distinct projection neuron subclasses is regulated by postnatal epigenetic modifications

eLife ◽

10.7554/elife.09531 ◽

2016 ◽

Vol 5 ◽

Cited By ~ 49

Author(s):

Kawssar Harb ◽

Elia Magrinelli ◽

Céline S Nicolas ◽

Nikita Lukianets ◽

Laura Frangeul ◽

...

Keyword(s):

Somatosensory Cortex ◽

Projection Neuron ◽

Projection Neurons ◽

Epigenetic Mechanisms ◽

Loss Of Function ◽

Long Distance ◽

Molecular Determinants ◽

Specific Manner ◽

Contralateral Cortex ◽

Callosal Projection

During cortical development, the identity of major classes of long-distance projection neurons is established by the expression of molecular determinants, which become gradually restricted and mutually exclusive. However, the mechanisms by which projection neurons acquire their final properties during postnatal stages are still poorly understood. In this study, we show that the number of neurons co-expressing Ctip2 and Satb2, respectively involved in the early specification of subcerebral and callosal projection neurons, progressively increases after birth in the somatosensory cortex. Ctip2/Satb2 postnatal co-localization defines two distinct neuronal subclasses projecting either to the contralateral cortex or to the brainstem suggesting that Ctip2/Satb2 co-expression may refine their properties rather than determine their identity. Gain- and loss-of-function approaches reveal that the transcriptional adaptor Lmo4 drives this maturation program through modulation of epigenetic mechanisms in a time- and area-specific manner, thereby indicating that a previously unknown genetic program postnatally promotes the acquisition of final subtype-specific features.

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miR-409-3p represses Cited2 at the evolutionary emergence of the callosal and corticospinal projections

10.1101/2021.11.03.467191 ◽

2021 ◽

Author(s):

Nikolaus R Wagner ◽

Ashis Sinha ◽

Verl B Siththanandan ◽

Angelica N Kowalchuk ◽

Jessica MacDonald ◽

...

Keyword(s):

Corpus Callosum ◽

Cognitive Abilities ◽

Molecular Mechanisms ◽

Deep Layer ◽

Projection Neuron ◽

Superficial Layer ◽

Projection Neurons ◽

Loss Of Function ◽

Full Extension ◽

Callosal Projection

Callosal projection neurons are a broad population of interhemispheric projection neurons that extend an axon across the corpus callosum to connect the two cerebral hemispheres. The corticospinal tract, comprised of the axons of corticospinal projection neurons, is unique to mammals, and its full extension to the lumbar segments that control walking is, like the corpus callosum, unique to placental mammals. The emergence of these two distinct axonal tracts is thought to underpin the evolutionary expansion of complex motor and cognitive abilities. The molecular mechanisms regulating the divergence of corticospinal and callosal projection neurons are incompletely understood. Our recent work identifies a genomic cluster of microRNAs (12qF1/Mirg) unique to placental mammals. These clustered miRNAs are specifically expressed by corticospinal vs. callosal projection neurons during the molecular refinement of corticospinal vs. callosal projection neuron fate (1). One of these, miR-409-3p, can convert layer V callosal into corticospinal projection neurons, acting in part through repression of the callosal-expressed transcriptional regulator Lmo4. This conversion is partial, however, suggesting that miR-409-3p represses multiple callosal projection neuron control genes in order to specify corticospinal projection neurons. One potential additional target of miR-409-3p repression is the callosal-expressed transcriptional co-activator Cited2. Cited2 interacts genetically with Lmo4, and Lmo4 can partially functionally compensate for Cited2 in thymus development(2). Further, Cited2 and Lmo4 function as opposing molecular controls over specific areal identity within superficial layer callosal projection neurons of the somatosensory and motor cortices, respectively (3). Cited2 is highly expressed by callosal, relative to corticospinal, projection neurons from the earliest stages of neurogenesis. Cited2 is necessary for the expansion of intermediate progenitor cells (IPCs) in the subventricular zone (SVZ), and the resulting generation of superficial layer callosal projection neurons. Here we show that miR-409-3p and Cited2 interact in IPCs and in corticospinal vs. deep layer callosal projection neuron development. miR-409-3p represses the Cited2 3UTR in luciferase assays. Mirg, which encodes miR-409-3p, and Cited2, are reciprocally expressed in IPCs at e15.5 by qPCR. Furthermore, miR-409-3p gain-of-function results in a phenocopy of established Cited2 loss-of-function in IPCs. Later on, miR-409-3p and Cited2 exert opposing effects on the adoption of corticospinal vs. callosal projection neuron subtype identity. Taken together, our work suggests that miR-409-3p, and possibly other 12qF1 miRNAs, represses Cited2 in IPCs to limit their proliferation, and in developing corticospinal and deep layer callosal projection neurons to favor corticospinal fate.

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Regulation des Angstverhaltens — zur Rolle neuronaler Netzwerke

BIOspektrum ◽

10.1007/s12268-019-0226-8 ◽

2019 ◽

Vol 25 (7) ◽

pp. 711-714

Author(s):

Nina Dedic ◽

Jan M. Deussing

Keyword(s):

Stress Response ◽

Ventral Tegmental Area ◽

Long Range ◽

Dopamine Release ◽

Receptor Type ◽

Projection Neurons ◽

Neuronal Circuit ◽

Brain Reward ◽

Crh Receptor Type 1

AbstractThe corticotropin-releasing hormone (CRH) system orchestrates the organism’s stress response including the regulation of adaptive be haviours. Here we describe a novel neuronal circuit, which acts anxiety suppressing and positively modulates dopamine release. This anxiolytic circuit comprises inhibitory CRH-expressing, long-range projection neurons within the extended amygdala. These neurons innervate the ventral tegmental area, a prominent brain reward center that expresses high levels of CRH receptor type 1.

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Differential Involvement of Projection Neurons During Emergence of Spontaneous Activity in the Developing Avian Hindbrain

Journal of Neurophysiology ◽

10.1152/jn.90835.2008 ◽

2009 ◽

Vol 101 (2) ◽

pp. 591-602 ◽

Cited By ~ 4

Author(s):

Hiraku Mochida ◽

Gilles Fortin ◽

Jean Champagnat ◽

Joel C. Glover

Keyword(s):

Spontaneous Activity ◽

Projection Neuron ◽

Projection Neurons ◽

Charge Coupled Device ◽

Neuron Populations ◽

Motor Nerves ◽

Differential Involvement ◽

A Charge ◽

The Brain ◽

Calcium Green

To better characterize the emergence of spontaneous neuronal activity in the developing hindbrain, spontaneous activity was recorded optically from defined projection neuron populations in isolated preparations of the brain stem of the chicken embryo. Ipsilaterally projecting reticulospinal (RS) neurons and several groups of vestibuloocular (VO) neurons were labeled retrogradely with Calcium Green-1 dextran amine and spontaneous calcium transients were recorded using a charge-coupled-device camera mounted on a fluorescence microscope. Simultaneous extracellular recordings were made from one of the trigeminal motor nerves (nV) to register the occurrence of spontaneous synchronous bursts of activity. Two types of spontaneous activity were observed: synchronous events (SEs), which occurred in register with spontaneous bursts in nV once every few minutes and were tetrodotoxin (TTX) dependent, and asynchronous events (AEs), which occurred in the intervals between SEs and were TTX resistant. AEs occurred developmentally before SEs and were in general smaller and more variable in amplitude than SEs. SEs appeared at the same stage as nV bursts early on embryonic day 4, first in RS neurons and then in VO neurons. All RS neurons participated equally in SEs from the outset, whereas different subpopulations of VO neurons participated differentially, both in terms of the proportion of neurons that exhibited SEs, the fidelity with which the SEs in individual neurons followed the nV bursts, and the developmental stage at which SEs appeared and matured. The results show that spontaneous activity is expressed heterogeneously among hindbrain projection neuron populations, suggesting its differential involvement in the formation of different functional neuronal circuits.

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Effects of Ginger Phenylpropanoids and Quercetin on Nrf2-ARE Pathway in Human BJ Fibroblasts and HaCaT Keratinocytes

BioMed Research International ◽

10.1155/2016/2173275 ◽

2016 ◽

Vol 2016 ◽

pp. 1-6 ◽

Cited By ~ 20

Author(s):

Ermin Schadich ◽

Jan Hlaváč ◽

Tereza Volná ◽

Lakshman Varanasi ◽

Marián Hajdúch ◽

...

Keyword(s):

Constitutive Expression ◽

Antioxidant Response ◽

Luciferase Reporter ◽

Related Factor ◽

Hacat Cells ◽

Hacat Keratinocytes ◽

Glutathione S Transferase ◽

Detoxification Enzyme ◽

Downstream Target ◽

Downstream Effector

Quercetin and phenylpropanoids are well known chemoprotective compounds identified in many plants. This study was aimed at determining their effects on activation of Nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant response element (Nrf2-ARE) signalling pathway and expression of its important downstream effector phase II detoxification enzyme glutathione-S-transferase P1 (GSTP1) in BJ foreskin fibroblasts and skin HaCaT keratinocytes. Cell lines and their corresponding Nrf2-ARE luciferase reporter cells were treated by ginger phenylpropanoids and quercetin for 10 h and the level of Nrf2 activity was subsequently determined. Both, ginger phenylpropanoids and quercetin, significantly increased the level of Nrf2 activity. Subsequent western blot analyses of proteins showed the increased expression level of glutathione-S-transferase P1 (GSTP1) in BJ cells but not in HaCaT cells. Such phenomenon of unresponsive downstream target expression in HaCaT cells was consistent with previous studies showing a constitutive expression of their GSTP1. Thus, while both ginger phenylpropanoids and quercetin have the property of increasing the level of Nrf2 both in HaCaT and in BJ cells, their effects on its downstream signalling were mediated only in BJ cells.

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Tonic engagement of nicotinic receptors bidirectionally controls striatal spiny projection neuron spike timing

10.1101/2021.11.02.466870 ◽

2021 ◽

Author(s):

Lior Matityahu ◽

Jeffrey Malgady ◽

Meital Schirelman ◽

Yvonne Johansson ◽

Jennifer Wilking ◽

...

Keyword(s):

Nicotinic Acetylcholine Receptors ◽

Acetylcholine Receptors ◽

Gaba Release ◽

Projection Neuron ◽

Spike Timing ◽

Projection Neurons ◽

Striatal Slices ◽

Cholinergic Interneurons ◽

Α7 Nachr ◽

Α7 Nachrs

Striatal spiny projection neurons (SPNs) transform convergent excitatory corticostriatal inputs into an inhibitory signal that shapes basal ganglia output. This process is fine-tuned by striatal GABAergic interneurons (GINs), which receive overlapping cortical inputs and mediate rapid corticostriatal feedforward inhibition of SPNs. Adding another level of control, cholinergic interneurons (CINs), which are also vigorously activated by corticostriatal excitation, can 1) disynaptically inhibit SPNs by activating α4β2 nicotinic acetylcholine receptors (nAChRs) on various GINs and 2) directly modulate corticostriatal synaptic strength via pre-synaptic α7 nAChR receptors. Measurements of the disynaptic inhibitory pathway, however, indicate that it is too slow to compete with direct GIN-mediated feed-forward inhibition. Moreover, functional nAChRs are also present on populations of GINs that do not respond to phasic activation of CINs, such as parvalbumin-positive fast-spiking interneurons (PV-FSIs), making the overall role of nAChRs in shaping striatal synaptic integration unclear. Using acute striatal slices we show that upon synchronous optogenetic activation of corticostriatal projections, blockade of α7 nAChRs delayed SPN spikes, whereas blockade of α4β2 nAChRs advanced SPN spikes and increased postsynaptic depolarizations. The nAChR-dependent inhibition was mediated by downstream GABA release, and data suggest that the GABA source was not limited to GINs that respond to phasic CIN activation. In particular, the observed spike-advancement caused by nAChR blockade was associated with a diminished frequency of spontaneous inhibitory postsynaptic currents in SPNs, and a parallel hyperpolarization of PV-FSIs. Taken together, we describe opposing roles for tonic (as opposed to phasic) engagement of nAChRs in striatal function. We conclude that tonic activation of nAChRs by CINs both sharpens the temporal fidelity of corticostriatal signaling via pre-synaptic α7 nAChRs and maintains a GABAergic brake on cortically-driven striatal output, processes that may shape SPN spike timing, striatal processing and synaptic plasticity.

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TCF7L1 promotes skin tumorigenesis independently of β-catenin through induction of LCN2

eLife ◽

10.7554/elife.23242 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 7

Author(s):

Amy T Ku ◽

Timothy M Shaver ◽

Ajay S Rao ◽

Jeffrey M Howard ◽

Christine N Rodriguez ◽

...

Keyword(s):

Tumor Growth ◽

Embryonic Stem ◽

Xenograft Model ◽

Transcriptome Profiling ◽

Loss Of Function ◽

Skin Tumorigenesis ◽

Oncogenic Ras ◽

Downstream Effector ◽

Skin Squamous Cell Carcinoma ◽

Chemically Induced

The transcription factor TCF7L1 is an embryonic stem cell signature gene that is upregulated in multiple aggressive cancer types, but its role in skin tumorigenesis has not yet been defined. Here we document TCF7L1 upregulation in skin squamous cell carcinoma (SCC) and demonstrate that TCF7L1 overexpression increases tumor incidence, tumor multiplicity, and malignant progression in the chemically induced mouse model of skin SCC. Additionally, we show that downregulation of TCF7L1 and its paralogue TCF7L2 reduces tumor growth in a xenograft model of human skin SCC. Using separation-of-function mutants, we show that TCF7L1 promotes tumor growth, enhances cell migration, and overrides oncogenic RAS-induced senescence independently of its interaction with β-catenin. Through transcriptome profiling and combined gain- and loss-of-function studies, we identified LCN2 as a major downstream effector of TCF7L1 that drives tumor growth. Our findings establish a tumor-promoting role for TCF7L1 in skin and elucidate the mechanisms underlying its tumorigenic capacity.

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Extracellular spreading of Wingless is required for Drosophila oogenesis

PLoS Genetics ◽

10.1371/journal.pgen.1009469 ◽

2021 ◽

Vol 17 (4) ◽

pp. e1009469

Author(s):

Xiaoxi Wang ◽

Kimberly S. LaFever ◽

Indrayani Waghmare ◽

Andrea Page-McCaw

Keyword(s):

Stem Cells ◽

Wnt Signaling ◽

Long Range ◽

Wing Disc ◽

Secreted Protein ◽

Loss Of Function ◽

Drosophila Oogenesis ◽

Central Source ◽

Follicle Stem Cells

Recent studies have investigated whether the Wnt family of extracellular ligands can signal at long range, spreading from their source and acting as morphogens, or whether they signal only in a juxtacrine manner to neighboring cells. The original evidence for long-range Wnt signaling arose from studies of Wg, a Drosophila Wnt protein, which patterns the wing disc over several cell diameters from a central source of Wg ligand. However, the requirement of long-range Wg for patterning was called into question when it was reported that replacing the secreted protein Wg with a membrane-tethered version, NRT-Wg, results in flies with normally patterned wings. We and others previously reported that Wg spreads in the ovary about 50 μm or 5 cell diameters, from the cap cells to the follicle stem cells (FSCs) and that Wg stimulates FSC proliferation. We used the NRT-wg flies to analyze the consequence of tethering Wg to the cap cells. NRT-wg homozygous flies are sickly, but we found that hemizygous NRT-wg/null flies, carrying only one copy of tethered Wingless, were significantly healthier. Despite their overall improved health, these hemizygous flies displayed dramatic reductions in fertility and in FSC proliferation. Further, FSC proliferation was nearly undetectable when the wg locus was converted to NRT-wg only in adults, and the resulting germarium phenotype was consistent with a previously reported wg loss-of-function phenotype. We conclude that Wg protein spreads from its source cells in the germarium to promote FSC proliferation.

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