scholarly journals Crosstalk with keratinocytes causes GNAQ oncogene specificity in melanoma

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Oscar Urtatiz ◽  
Amanda Haage ◽  
Guy Tanentzapf ◽  
Catherine D Van Raamsdonk
Keyword(s):  
Central Nervous System ◽  
Novel Therapies ◽  
Cell Of Origin ◽  
Present Evidence ◽  
Uveal Tract ◽  
Suppressor Mutations ◽  
Interfollicular Epidermis ◽  
Melanoma Subtypes ◽  
Overlapping Sets ◽  
Common Cell

Different melanoma subtypes exhibit specific and non-overlapping sets of oncogene and tumor suppressor mutations, despite a common cell of origin in melanocytes. For example, activation of the Gαq/11 signaling pathway is a characteristic initiating event in primary melanomas that arise in the dermis, uveal tract or central nervous system. It is rare in melanomas arising in the epidermis. The mechanism for this specificity is unknown. Here, we present evidence that in the mouse, crosstalk with the epidermal microenvironment actively impairs the survival of melanocytes expressing the GNAQQ209L oncogene. We found that GNAQQ209L, in combination with signaling from the interfollicular epidermis (IFE), stimulates dendrite extension, leads to actin cytoskeleton disorganization, inhibits proliferation and promotes apoptosis in melanocytes. The effect was reversible and paracrine. In contrast, the epidermal environment increased the survival of wildtype and BrafV600E expressing melanocytes. Hence, our studies reveal the flip side of Gaq/11 signaling, which was hitherto unsuspected. In the future, the identification of the epidermal signals that restrain the GNAQQ209L oncogene could suggest novel therapies for GNAQ and GNA11 mutant melanomas.

scholarly journals Crosstalk with keratinocytes causes GNAQ oncogene specificity in melanoma

2021 ◽  
Author(s):  
Oscar Urtatiz ◽  
Amanda Haage ◽  
Guy Tanentzapf ◽  
Catherine D. Van Raamsdonk
Keyword(s):  
Signaling Pathway ◽  
Gene Expression Analysis ◽  
Cell Of Origin ◽  
Uveal Tract ◽  
Downstream Effector ◽  
Suppressor Mutations ◽  
Differential Gene ◽  
Melanoma Subtypes ◽  
Overlapping Sets ◽  
Common Cell

Different melanoma subtypes exhibit specific and non-overlapping sets of oncogene and tumor suppressor mutations, despite a common cell of origin in melanocytes. For example, activation of the Gαq/11 signaling pathway is a characteristic initiating event in primary melanomas that arise in the dermis, uveal tract or central nervous system. It is rare in melanomas arising in the epidermis. Here, we present evidence that in the mouse, crosstalk with the epidermal microenvironment actively impairs the survival of melanocytes expressing the GNAQQ209L oncogene, providing a new model for oncogene specificity in cancer. The presence of epidermal cells inhibited cell division and fragmented dendrites of melanocytes expressing GNAQQ209L in culture, while they promoted the growth of normal melanocytes. Differential gene expression analysis of FACS sorted epidermal melanocytes showed that cells expressing GNAQQ209L exhibit an oxidative stress and apoptosis signature previously linked to vitiligo. Furthermore, PLCB4, the direct downstream effector of Gαq/11 signaling, is frequently mutated in cutaneous melanoma alongside P53 and NF1. Our results suggest that a deficiency of PLCB4 promotes cutaneous melanomagenesis by reducing GNAQ driven signaling. Hence, our studies reveal the flip side of the GNAQ/PLCB4 signaling pathway, which was hitherto unsuspected. In the future, understanding how epidermal crosstalk restrains the GNAQQ209L oncogene could suggest novel melanoma therapies.

scholarly journals Phosphate Assimilation in Rhizobium(Sinorhizobium) meliloti: Identification of apit-Like Gene

1998 ◽  
Vol 180 (16) ◽  
pp. 4219-4226 ◽  
Author(s):  
Sylvie D. Bardin ◽  
Ralf T. Voegele ◽  
Turlough M. Finan
Keyword(s):  
Transport System ◽  
Sinorhizobium Meliloti ◽  
Rhizobium Meliloti ◽  
Root Nodules ◽  
Phosphate Transport ◽  
Wild Type ◽  
Transcription Start ◽  
Present Evidence ◽  
Suppressor Mutations ◽  
Mutant Cells

ABSTRACT Rhizobium meliloti mutants defective in thephoCDET-encoded phosphate transport system form root nodules on alfalfa plants that fail to fix nitrogen (Fix−). We have previously reported that two classes of second-site mutations can suppress the Fix− phenotype ofphoCDET mutants to Fix+. Here we show that one of these suppressor loci (sfx1) contains two genes, orfA and pit, which appear to form an operon transcribed in the order orfA-pit. The Pit protein is homologous to various phosphate transporters, and we present evidence that three suppressor mutations arose from a single thymidine deletion in a hepta-thymidine sequence centered 54 nucleotides upstream of the orfA transcription start site. This mutation increased the level of orfA-pit transcription. These data, together with previous biochemical evidence, show that theorfA-pit genes encode a Pi transport system that is expressed in wild-type cells grown with excess Pibut repressed in cells under conditions of Pi limitation. In phoCDET mutant cells, orfA-pitexpression is repressed, but this repression is alleviated by the second-site suppressor mutations. Suppression increasesorfA-pit expression compensating for the deficiencies in phosphate assimilation and symbiosis of the phoCDETmutants.

The somatic error hypothesis of anxiety

2018 ◽  
Author(s):  
Sahib S. Khalsa ◽  
Justin S. Feinstein
Keyword(s):  
Central Nervous System ◽  
Physiological State ◽  
Brain Regions ◽  
Novel Therapies ◽  
Body State ◽  
Long Term Changes ◽  
The Central Nervous System ◽  
And Behavior ◽  
The Brain

A regulatory battle for control ensues in the central nervous system following a mismatch between the current physiological state of an organism as mapped in viscerosensory brain regions and the predicted body state as computed in visceromotor control regions. The discrepancy between the predicted and current body state (i.e. the “somatic error”) signals a need for corrective action, motivating changes in both cognition and behavior. This chapter argues that anxiety disorders are fundamentally driven by somatic errors that fail to be adaptively regulated, leaving the organism in a state of dissonance where the predicted body state is perpetually out of line with the current body state. Repeated failures to quell somatic error can result in long-term changes to interoceptive circuitry within the brain. This chapter explores the neuropsychiatric sequelae that can emerge following chronic allostatic dysregulation of somatic errors and discusses novel therapies that might help to correct this dysregulation.

Segmentation of the central nervous system in leech

Development ◽  
2000 ◽  
Vol 127 (4) ◽  
pp. 735-744 ◽  
Author(s):  
D.H. Shain ◽  
D.K. Stuart ◽  
F.Z. Huang ◽  
D.A. Weisblat
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Blast Cell ◽  
Cell Behavior ◽  
Present Evidence ◽  
Primary Blast ◽  
Blast Cells ◽  
The Central Nervous System ◽  
Fissure Formation ◽  
The Relationship

Central nervous system (CNS) in leech comprises segmentally iterated progeny derived from five embryonic lineages (M, N, O, P and Q). Segmentation of the leech CNS is characterized by the formation of a series of transverse fissures that subdivide initially continuous columns of segmental founder cells in the N lineage into distinct ganglionic primordia. We have examined the relationship between the N lineage cells that separate to form the fissures and lateral ectodermal and mesodermal derivatives by differentially labeling cells with intracellular lineage tracers and antibodies. Although subsets of both lateral ectoderm and muscle fibers contact N lineage cells at or near the time of fissure formation, ablation experiments suggest that these contacts are not required for initiating fissure formation. It appears, therefore, that this aspect of segmentation occurs autonomously within the N lineage. To support this idea, we present evidence that fundamental differences exist between alternating ganglionic precursor cells (nf and ns primary blast cells) within the N lineage. Specifically, ablation of an nf primary blast cell sometimes resulted in the fusion of ipsilateral hemi-ganglia, while ablation of an ns primary blast cell often caused a ‘slippage’ of blast cells posterior to the lesion. Also, differences in cell behavior were observed in biochemically arrested nf and ns primary blast cells. Collectively, these results lead to a model of segmentation in the leech CNS that is based upon differences in cell adhesion and/or cell motility between the alternating nf and ns primary blast cells. We note that the segmentation processes described here occur well prior to the expression of the leech engrailed-class gene in the N lineage.

Central origin of the efferent neurons projecting to the eyes of Limulus polyphemus

1991 ◽  
Vol 6 (5) ◽  
pp. 481-495 ◽  
Author(s):  
B. G. Calman ◽  
B.- A. Battelle
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Optic Nerve ◽  
Optic Tract ◽  
Limulus Polyphemus ◽  
Cell Of Origin ◽  
Optic Nerves ◽  
Visual Cells ◽  
Efferent Neurons ◽  
The Central Nervous System

AbstractCircadian rhythms affect the anatomy, physiology, and biochemistry of the visual cells in the eyes of the horseshoe crab (Limulus polyphemus). These rhythms are mediated by the activity of efferent neurons that project from the central nervous system to all of the eyes. In this study, the optic nerves of Limulus were backfilled with Neurobiotin revealing the location of efferent cell bodies and their projections through the central nervous system. We propose that this efferent system mediates the circadian changes in visual functions in Limulus. Whether these cells are the circadian pacemaker neurons is unknown.The cell bodies of the efferent neurons are ovoid and have a diameter of 40−80 μm. They lie within the cheliceral ganglion of the tritocerebrum, just posterior to the protocerebrum. This ganglion is on the lateral edge of the circumesophageal ring, near the middle of the dorsal-ventral axis of the ring. Each optic nerve contains axons from both ipsilateral and contralateral efferent cells, and some, possibly all, of them project bilaterally and to more than one type of optic nerve.The efferent axons form a tract that projects anteriorly from the cell bodies to the protocerebrum, and bifurcates just lateral to the protocerebral bridge. One branch crosses the midline and projects anteriorly to the optic tract and medulla on the side contralateral to the cell of origin; the other branch follows a symmetric pathway on the ipsilateral side. Small branches arising from the major efferent axons in the optic tract project through the ocellar ganglia to the median optic nerves. The efferent axons branch again in the medulla, and some of these branches innervate the ventral optic nerves. The major branches of the efferent axons continue through the lamina and enter the lateral optic nerve.

scholarly journals Mesenchymal Lineage Heterogeneity Underlies Non-Redundant Functions of Pancreatic Cancer-Associated Fibroblasts

2021 ◽  
Author(s):  
Erin J. Helms ◽  
Mark W. Berry ◽  
R. Crystal Chaw ◽  
Christopher C. DuFort ◽  
Duanchen Sun ◽  
...  
Keyword(s):  
Pancreatic Stellate Cells ◽  
Ductal Adenocarcinoma ◽  
Cell Of Origin ◽  
Cellular Origin ◽  
Cancer Associated Fibroblast ◽  
Cells Of Origin ◽  
And Function ◽  
Redundant Functions ◽  
Common Cell

Cancer-associated fibroblast (CAF) heterogeneity is increasingly appreciated, but the origins and functions of distinct CAF subtypes remain poorly understood. The abundant and transcriptionally diverse CAF population in pancreatic ductal adenocarcinoma (PDAC) is thought to arise from a common cell of origin, pancreatic stellate cells (PSCs), with diversification resulting from cytokine and growth factor gradients within the tumor microenvironment. Here we analyzed the differentiation and function of PSCs during tumor progression in vivo. Contrary to expectations, we found that PSCs give rise to a numerically minor subset of PDAC CAFs. Targeted ablation of PSC-derived CAFs within their host tissue revealed non-redundant functions for this defined CAF population in shaping the PDAC microenvironment, including production of specific components of the extracellular matrix. Together, these findings link stromal evolution from distinct cells of origin to transcriptional heterogeneity among PDAC CAFs, and demonstrate unique functions for CAFs of a defined cellular origin.

VH Gene Sequences From Primary Central Nervous System Lymphomas Indicate Derivation From Highly Mutated Germinal Center B Cells With Ongoing Mutational Activity

Blood ◽  
1999 ◽  
Vol 94 (5) ◽  
pp. 1738-1746 ◽  
Author(s):  
Andrew R. Thompsett ◽  
David W. Ellison ◽  
Freda K. Stevenson ◽  
Delin Zhu
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
B Cell ◽  
Germinal Center ◽  
Central Nervous System Lymphoma ◽  
Mechanism Analysis ◽  
Cell Of Origin ◽  
B Cell Lymphomas ◽  
Vh Gene ◽  
The Brain

Primary central nervous system lymphoma (PCNSL) represents 1% to 3% intracranial tumors. Most PCNSL are located in the brain, and 75% are large B-cell lymphomas. The largest subgroup of these tumors contains cells that resemble centroblasts and has been labelled diffuse centroblastic (polymorphous) lymphoma. To investigate the cell of origin and the clonal history of these tumors, we have analyzed VH gene of 5 cases of PCNSL, all confirmed by histological studies to be Epstein-Barr virus (EBV)-negative, high-grade diffuse B-cell lymphomas. The V4-34 gene of the VH4 family was used in 4 of 5 cases. All VHgenes were found to have accumulated very high levels of somatic mutation (14% to 25%). In 3 of 5 cases, intraclonal nucleotide heterogeneity, including codon deletion in some clones in 1 case, was observed, indicating that the VH genes were still under the influence of the somatic hypermutation mechanism. Analysis of the distribution of silent and replacement mutations showed evidence for preservation of immunoglobulin structure in all cases. These results suggest that, although there is no evidence for germinal center formation in the brain tissue, PCNSL is derived from a B cell with features associated with location in a germinal center environment.

scholarly journals WNT5a Regulates Epithelial Morphogenesis in the Developing Choroid Plexus

2020 ◽  
Vol 30 (6) ◽  
pp. 3617-3631 ◽  
Author(s):  
Michael B Langford ◽  
Conor J O’Leary ◽  
Lenin Veeraval ◽  
Amanda White ◽  
Vanessa Lanoue ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Choroid Plexus ◽  
Cerebral Spinal Fluid ◽  
Epithelial Morphogenesis ◽  
Mammalian Brain ◽  
Cellular Mechanisms ◽  
Present Evidence ◽  
Cellular Processes ◽  
Rhoa Kinase ◽  
Important Regulator

Abstract The choroid plexus (CP) is the predominant supplier of cerebral spinal fluid (CSF) and the site of the blood–CSF barrier and is thus essential for brain development and central nervous system homeostasis. Despite these crucial roles, our understanding of the molecular and cellular processes giving rise to the CPs within the ventricles of the mammalian brain is very rudimentary. Here, we identify WNT5a as an important regulator of CP development, where it acts as a pivotal factor driving CP epithelial morphogenesis in all ventricles. We show that WNT5a is essential for the establishment of a cohesive epithelium in the developing CP. We find that in its absence all CPs are substantially reduced in size and complexity and fail to expand into the ventricles. Severe defects were observed in the epithelial cytoarchitecture of all Wnt5a−/− CPs, exemplified by loss of apicobasally polarized morphology and detachment from the ventricular surface and/or basement membrane. We also present evidence that the WNT5a receptor, RYK, and the RHOA kinase, ROCK, are required for normal CP epithelial morphogenesis. Our study, therefore, reveals important insights into the molecular and cellular mechanisms governing CP development.

scholarly journals An Update on the Cellular and Molecular Biology of Brain Tumors

1989 ◽  
Vol 16 (1) ◽  
pp. 22-27 ◽  
Author(s):  
Michael D. Cusimano
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Patient Management ◽  
Positive Impact ◽  
Growth Inhibitor ◽  
Present Knowledge ◽  
Cellular Biology ◽  
Novel Therapies ◽  
The Central Nervous System ◽  
Inhibitor Genes

ABSTRACT:Patients with tumors of the central nervous system (CNS) remain difficult to treat despite recent advances in surgical, chemotherapeutic and radiotherapeutic techniques. A better understanding of the molecular and cellular biology of neoplasia is providing neuroscientists with a framework on which to devise novel therapies for these patients. It thus becomes imperative that neurologists and neurosurgeons be aware of these advances in basic science that may eventually have a positive impact on patient management. This paper reviews our present knowledge of the process of CNS oncogenesis and the roles that chemicals, viruses, oncogenes, growth inhibitor genes, and growth factors play in the process.

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