Co-reporter:Yun C. Yung;Blue B. Lake;Gwendolyn E. Kaeser;Neeraj S. Salathia;Rizi Ai;Andre Wildberg;Derek Gao;Song Chen;Ho-Lim Fung;Jian-Bing Fan;Allison Chen;Mostafa Ronaghi;Wei Wang;Richard Shen;Julian Wong;Rui Liu;Raakhee Vijayaraghavan;Fiona Kaper;Xiaoyan Sheng;Kun Zhang
Science 2016 Volume 352(Issue 6293) pp:
Publication Date(Web):
DOI:10.1126/science.aaf1204
Single-nucleus gene expression
Identifying the genes expressed at the level of a single cell nucleus can better help us understand the human brain. Blue et al. developed a single-nuclei sequencing technique, which they applied to cells in classically defined Brodmann areas from a postmortem brain. Clustering of gene expression showed concordance with the area of origin and defining 16 neuronal subtypes. Both excitatory and inhibitory neuronal subtypes show regional variations that define distinct cortical areas and exhibit how gene expression clusters may distinguish between distinct cortical areas. This method opens the door to widespread sampling of the genes expressed in a diseased brain and other tissues of interest.
Science, this issue p. 1586
Co-reporter:H Mirendil, E A Thomas, C De Loera, K Okada, Y Inomata and J Chun
Translational Psychiatry 2015 Volume 5(Apr) pp:e541
Publication Date(Web):2015-04-01
DOI:10.1038/tp.2015.33
Genetic, environmental and neurodevelopmental factors are thought to underlie the onset of neuropsychiatric disorders such as schizophrenia. How these risk factors collectively contribute to pathology is unclear. Here, we present a mouse model of prenatal intracerebral hemorrhage—an identified risk factor for schizophrenia—using a serum-exposure paradigm. This model exhibits behavioral, neurochemical and schizophrenia-related gene expression alterations in adult females. Behavioral alterations in amphetamine-induced locomotion, prepulse inhibition, thigmotaxis and social interaction—in addition to increases in tyrosine hydroxylase-positive dopaminergic cells in the substantia nigra and ventral tegmental area and decreases in parvalbumin-positive cells in the prefrontal cortex—were induced upon prenatal serum exposure. Lysophosphatidic acid (LPA), a lipid component of serum, was identified as a key molecular initiator of schizophrenia-like sequelae induced by serum. Prenatal exposure to LPA alone phenocopied many of the schizophrenia-like alterations seen in the serum model, whereas pretreatment with an antagonist against the LPA receptor subtype LPA1 prevented many of the behavioral and neurochemical alterations. In addition, both prenatal serum and LPA exposure altered the expression of many genes and pathways related to schizophrenia, including the expression of Grin2b, Slc17a7 and Grid1. These findings demonstrate that aberrant LPA receptor signaling associated with fetal brain hemorrhage may contribute to the development of some neuropsychiatric disorders.
Co-reporter:Yasuyuki Kihara;Michael Maceyka;Sarah Spiegel
British Journal of Pharmacology 2014 Volume 171( Issue 15) pp:3575-3594
Publication Date(Web):
DOI:10.1111/bph.12678
Lysophospholipids encompass a diverse range of small, membrane-derived phospholipids that act as extracellular signals. The signalling properties are mediated by 7-transmembrane GPCRs, constituent members of which have continued to be identified after their initial discovery in the mid-1990s. Here we briefly review this class of receptors, with a particular emphasis on their protein and gene nomenclatures that reflect their cognate ligands. There are six lysophospholipid receptors that interact with lysophosphatidic acid (LPA): protein names LPA1 – LPA6 and italicized gene names LPAR1-LPAR6 (human) and Lpar1-Lpar6 (non-human). There are five sphingosine 1-phosphate (S1P) receptors: protein names S1P1-S1P5 and italicized gene names S1PR1-S1PR5 (human) and S1pr1-S1pr5 (non-human). Recent additions to the lysophospholipid receptor family have resulted in the proposed names for a lysophosphatidyl inositol (LPI) receptor – protein name LPI1 and gene name LPIR1 (human) and Lpir1 (non-human) – and three lysophosphatidyl serine receptors – protein names LyPS1, LyPS2, LyPS3 and gene names LYPSR1-LYPSR3 (human) and Lypsr1-Lypsr3 (non-human) along with a variant form that does not appear to exist in humans that is provisionally named LyPS2L. This nomenclature incorporates previous recommendations from the International Union of Basic and Clinical Pharmacology, the Human Genome Organization, the Gene Nomenclature Committee, and the Mouse Genome Informatix.
Co-reporter:Tetsuji Mutoh;Richard Rivera
British Journal of Pharmacology 2012 Volume 165( Issue 4) pp:829-844
Publication Date(Web):
DOI:10.1111/j.1476-5381.2011.01622.x
The discovery of lysophospholipid (LP) 7-transmembrane, G protein-coupled receptors (GPCRs) that began in the 1990s, together with research into the functional roles of the major LPs known as lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P), have opened new research avenues into their biological processes and mechanisms. Major examples of LP signalling effects include embryogenesis, nervous system development, vascular development, uterine implantation, immune cell trafficking, and inflammatory reactions. LP signalling also influences the pathophysiology of many diseases including cancer, autoimmune and inflammatory diseases, which indicate that LP receptors may be attractive targets for pharmacological therapies. A key example of such a therapeutic agent is the S1P receptor modulator FTY720, which upon phosphorylation and continued drug exposure, acts as an S1P receptor functional antagonist. This compound (also known as fingolimod or Gilenya) has recently been approved by the FDA for the treatment of relapsing forms of multiple sclerosis. Continued basic and translational research on LP signalling should provide novel insights into both basic biological mechanisms, as well as novel therapeutic approaches to combat a range of human diseases.
Co-reporter:Yun C. Yung;Tetsuji Mutoh;Kyoko Noguchi;Mu-En Lin;Ji Woong Choi;Richard R. Rivera;Marcy A. Kingsbury
Science Translational Medicine 2011 Volume 3(Issue 99) pp:99ra87
Publication Date(Web):07 Sep 2011
DOI:10.1126/scitranslmed.3002095
Blockade of lysophosphatidic acid signaling provides a new strategy for treating fetal hydrocephalus.
Co-reporter:Keira Joann Herr;Deron R. Herr;Chang-Wook Lee;Kyoko Noguchi
PNAS 2011 Volume 108 (Issue 37 ) pp:15444-15449
Publication Date(Web):2011-09-13
DOI:10.1073/pnas.1106129108
Fetal hypoxia is a common risk factor that has been associated with a range of CNS disorders including epilepsy, schizophrenia,
and autism. Cellular and molecular mechanisms through which hypoxia may damage the developing brain are incompletely understood
but are likely to involve disruption of the laminar organization of the cerebral cortex. Lysophosphatidic acid (LPA) is a
bioactive lipid capable of cortical influences via one or more of six cognate G protein-coupled receptors, LPA1–6, several of which are enriched in fetal neural progenitor cells (NPCs). Here we report that fetal hypoxia induces cortical
disruption via increased LPA1 signaling involving stereotyped effects on NPCs: N-cadherin disruption, displacement of mitotic NPCs, and impaired neuronal migration, as assessed both ex vivo and in vivo.
Importantly, genetic removal or pharmacological inhibition of LPA1 prevented the occurrence of these hypoxia-induced phenomena. Hypoxia resulted in overactivation of LPA1 through selective inhibition of G protein-coupled receptor kinase 2 expression and activation of downstream pathways including
Gαi and Ras-related C3 botulinum toxin substrate 1. These data identify stereotyped and selective hypoxia-induced cerebral cortical
disruption requiring LPA1 signaling, inhibition of which can reduce or prevent disease-associated sequelae, and may take us closer to therapeutic treatment
of fetal hypoxia-induced CNS disorders and possibly other forms of hypoxic injury.
Co-reporter:Shannon E. Gardell;Ji Woong Choi;Deron R. Herr;Chang-Wook Lee;Kyoko Noguchi;Richard Rivera;Siew Teng Teo;Yun C. Yung;Melissa Lu;Grace Kennedy
PNAS 2011 Volume 108 (Issue 2 ) pp:751-756
Publication Date(Web):2011-01-11
DOI:10.1073/pnas.1014154108
Sphingosine 1-phosphate (S1P), a lysophospholipid, has gained relevance to multiple sclerosis through the discovery of FTY720
(fingolimod), recently approved as an oral treatment for relapsing forms of multiple sclerosis. Its mechanism of action is
thought to be immunological through an active phosphorylated metabolite, FTY720-P, that resembles S1P and alters lymphocyte
trafficking through receptor subtype S1P1. However, previously reported expression and in vitro studies of S1P receptors suggested that direct CNS effects of FTY720
might theoretically occur through receptor modulation on neurons and glia. To identify CNS cells functionally contributing
to FTY720 activity, genetic approaches were combined with cellular and molecular analyses. These studies relied on the functional
assessment, based on clinical score, of conditional null mouse mutants lacking S1P1 in CNS cell lineages and challenged by experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis.
All conditional null mutants displayed WT lymphocyte trafficking that responded normally to FTY720. In marked contrast, EAE
was attenuated and FTY720 efficacy was lost in CNS mutants lacking S1P1 on GFAP-expressing astrocytes but not on neurons. In situ hybridization studies confirmed that astrocyte loss of S1P1 was the key alteration in functionally affected mutants. Reductions in EAE clinical scores were paralleled by reductions
in demyelination, axonal loss, and astrogliosis. Receptor rescue and pharmacological experiments supported the loss of S1P1 on astrocytes through functional antagonism by FTY720-P as a primary FTY720 mechanism. These data identify nonimmunological
CNS mechanisms of FTY720 efficacy and implicate S1P signaling pathways within the CNS as targets for multiple sclerosis therapies.
Co-reporter:Michael J McConnell;Hugh R MacMillan
Neural Development 2009 Volume 4( Issue 1) pp:
Publication Date(Web):2009 December
DOI:10.1186/1749-8104-4-28
Existing quantitative models of mouse cerebral cortical development are not fully constrained by experimental data.Here, we use simple difference equations to model neural progenitor cell fate decisions, incorporating intermediate progenitor cells and initially low rates of neural progenitor cell death. Also, we conduct a sensitivity analysis to investigate possible uncertainty in the fraction of cells that divide, differentiate, and die at each cell cycle.We demonstrate that uniformly low-level neural progenitor cell death, as concluded in previous models, is incompatible with normal mouse cortical development. Levels of neural progenitor cell death up to and exceeding 50% are compatible with normal cortical development and may operate to prevent forebrain overgrowth as observed following cell death attenuation, as occurs in caspase 3-null mutant mice.
Co-reporter:M. A. Kingsbury;M. J. McConnell;B. Friedman;D. Kaushal;A. H. Yang;S. K. Rehen;J. Chun
PNAS 2005 Volume 102 (Issue 17 ) pp:6143-6147
Publication Date(Web):2005-04-26
DOI:10.1073/pnas.0408171102
The existence of aneuploid cells within the mammalian brain has suggested the influence of genetic mosaicism on normal neural
circuitry. However, aneuploid cells might instead be glia, nonneural, or dying cells, which are irrelevant to direct neuronal
signaling. Combining retrograde labeling with FISH for chromosome-specific loci, distantly labeled aneuploid neurons were
observed in expected anatomical projection areas. Coincident labeling for immediate early gene expression indicated that these
aneuploid neurons were functionally active. These results demonstrate that functioning neurons with aneuploid genomes form
genetically mosaic neural circuitries as part of the normal organization of the mammalian brain.
Co-reporter:Xiaoqin Ye;Kotaro Hama;James J. A. Contos;Brigitte Anliker;Asuka Inoue;Michael K. Skinner;Hiroshi Suzuki;Tomokazu Amano;Grace Kennedy;Hiroyuki Arai;Junken Aoki
Nature 2005 435(7038) pp:104-108
Publication Date(Web):2005-05-05
DOI:10.1038/nature03505
Every successful pregnancy requires proper embryo implantation. Low implantation rate is a major problem during infertility treatments using assisted reproductive technologies1. Here we report a newly discovered molecular influence on implantation through the lysophosphatidic acid (LPA) receptor LPA3 (refs 2–4). Targeted deletion of LPA3 in mice resulted in significantly reduced litter size, which could be attributed to delayed implantation and altered embryo spacing. These two events led to delayed embryonic development, hypertrophic placentas shared by multiple embryos and embryonic death. An enzyme demonstrated to influence implantation, cyclooxygenase 2 (COX2) (ref. 5), was downregulated in LPA3-deficient uteri during pre-implantation. Downregulation of COX2 led to reduced levels of prostaglandins E2 and I2 (PGE2 and PGI2), which are critical for implantation1. Exogenous administration of PGE2 or carbaprostacyclin (a stable analogue of PGI2) into LPA3-deficient female mice rescued delayed implantation but did not rescue defects in embryo spacing. These data identify LPA3 receptor-mediated signalling as having an influence on implantation, and further indicate linkage between LPA signalling and prostaglandin biosynthesis.
Co-reporter:
Nature Neuroscience 2004 7(4) pp:323-325
Publication Date(Web):
DOI:10.1038/nn0404-323
Individual olfactory sensory neurons express only one of more than a thousand different odorant receptors, suggesting that DNA rearrangement may be involved. Based on a clever new technical approach, two groups now conclude that this is not the case.
Co-reporter:
Nature Neuroscience 2003 6(12) pp:1292-1299
Publication Date(Web):16 November 2003
DOI:10.1038/nn1157
Lysophosphatidic acid (LPA) is a phospholipid that has extracellular signaling properties mediated by G protein−coupled receptors. Two LPA receptors, LPA1 and LPA2, are expressed in the embryonic cerebral cortex, suggesting roles for LPA signaling in cortical formation. Here we report that intact cerebral cortices exposed to extracellular LPA ex vivo rapidly increased in width and produced folds resembling gyri, which are not normally present in mouse brains and are absent in LPA1 LPA2 double-null mice. Mechanistically, growth was not due to increased proliferation but rather to receptor-dependent reduced cell death and increased terminal mitosis of neural progenitor cells (NPCs). Our results implicate extracellular lipid signals as new influences on brain formation during embryonic development.
Co-reporter:Xiaoqin Ye, Jerold Chun
Trends in Endocrinology & Metabolism (January 2010) Volume 21(Issue 1) pp:17-24
Publication Date(Web):1 January 2010
DOI:10.1016/j.tem.2009.08.003
Lysophosphatidic acid (LPA) is a cell membrane phospholipid metabolite that can act as an extracellular signal. Its effects are mediated through at least five G protein-coupled receptors, LPA1–5, and probably others as well. Studies in multiple species including LPAR-deficient mice and humans have identified or implicated important roles for receptor-mediated LPA signaling in multiple aspects of vertebrate reproduction. These include ovarian function, spermatogenesis, fertilization, early embryo development, embryo implantation, embryo spacing, decidualization, pregnancy maintenance and parturition. LPA signaling can also have pathological consequences, influencing aspects of endometriosis and ovarian cancer. Here we review recent progress in LPA signaling research relevant to female and male reproduction.
Co-reporter:Diane M. Bushman, Jerold Chun
Seminars in Cell & Developmental Biology (April 2013) Volume 24(Issue 4) pp:357-369
Publication Date(Web):1 April 2013
DOI:10.1016/j.semcdb.2013.02.003
Genomically identical cells have long been assumed to comprise the human brain, with post-genomic mechanisms giving rise to its enormous diversity, complexity, and disease susceptibility. However, the identification of neural cells containing somatically generated mosaic aneuploidy – loss and/or gain of chromosomes from a euploid complement – and other genomic variations including LINE1 retrotransposons and regional patterns of DNA content variation (DCV), demonstrate that the brain is genomically heterogeneous. The precise phenotypes and functions produced by genomic mosaicism are not well understood, although the effects of constitutive aberrations, as observed in Down syndrome, implicate roles for defined mosaic genomes relevant to cellular survival, differentiation potential, stem cell biology, and brain organization. Here we discuss genomic mosaicism as a feature of the normal brain as well as a possible factor in the weak or complex genetic linkages observed for many of the most common forms of neurological and psychiatric diseases.Highlights► Developing and mature brains are composed of cells that can be genomically varied and mosaic. ► Mosaic aneuploidy, as part of DNA content variation (DCV), along with their analyses in brain cells are described. ► Functions for neural genomic mosaicism are discussed; roles in cell death and survival implicate selection mechanisms. ► The relevance of mosaic genomic variation to neurological and psychiatric disorders is discussed.
Co-reporter:Mu-En Lin, Deron R. Herr, Jerold Chun
Prostaglandins & Other Lipid Mediators (April 2010) Volume 91(Issues 3–4) pp:130-138
Publication Date(Web):1 April 2010
DOI:10.1016/j.prostaglandins.2009.02.002
Lysophosphatidic acid (LPA), a water-soluble phospholipid, has gained significant attention in recent years since the discovery that it acts as a potent signaling molecule with wide-ranging effects on many different target tissues. There are currently five identified G protein-coupled receptors for LPA and more are undergoing validation. The complexity of the expression pattern and signaling properties of LPA receptors results in multiple influences on developmental, physiological, and pathological processes. This review provides a summary of LPA receptor signaling and current views on the potential involvement of this pathway in human diseases that include cardiovascular, cancer, neuropathic pain, neuropsychiatric disorders, reproductive disorders, and fibrosis. The involvement of LPA signaling in these processes implicates multiple, potential drug targets including LPA receptor subtypes and LPA metabolizing enzymes. Modulation of LPA signaling may thus provide therapeutic inroads for the treatment of human disease.
Co-reporter:Yun C. Yung, Nicole C. Stoddard, Hope Mirendil, Jerold Chun
Neuron (8 April 2015) Volume 86(Issue 1) pp:341
Publication Date(Web):8 April 2015
DOI:10.1016/j.neuron.2015.03.043
Co-reporter:Yun C. Yung, Nicole C. Stoddard, Hope Mirendil, Jerold Chun
Neuron (18 February 2015) Volume 85(Issue 4) pp:669-682
Publication Date(Web):18 February 2015
DOI:10.1016/j.neuron.2015.01.009
The brain is composed of many lipids with varied forms that serve not only as structural components but also as essential signaling molecules. Lysophosphatidic acid (LPA) is an important bioactive lipid species that is part of the lysophospholipid (LP) family. LPA is primarily derived from membrane phospholipids and signals through six cognate G protein-coupled receptors (GPCRs), LPA1-6. These receptors are expressed on most cell types within central and peripheral nervous tissues and have been functionally linked to many neural processes and pathways. This Review covers a current understanding of LPA signaling in the nervous system, with particular focus on the relevance of LPA to both physiological and diseased states.
Co-reporter:Aran Groves, Yasuyuki Kihara, Jerold Chun
Journal of the Neurological Sciences (15 May 2013) Volume 328(Issues 1–2) pp:9-18
Publication Date(Web):15 May 2013
DOI:10.1016/j.jns.2013.02.011
Fingolimod is the first oral disease-modifying therapy approved for relapsing forms of multiple sclerosis (MS). Following phosphorylation in vivo, the active agent, fingolimod phosphate (fingolimod-P), acts as a sphingosine 1-phosphate (S1P) receptor modulator, binding with high affinity to four of the five known S1P receptors (S1P1, S1P3, S1P4 and S1P5). The mechanism of action of fingolimod in MS has primarily been considered as immunomodulatory, whereby fingolimod-P modulates S1P1 on lymphocytes, selectively retaining autoreactive lymphocytes in lymph nodes to reduce damaging infiltration into the central nervous system (CNS). However, emerging evidence indicates that fingolimod has direct effects in the CNS in MS. For example, in the MS animal model of experimental autoimmune encephalomyelitis (EAE), fingolimod is highly efficacious in both a prophylactic and therapeutic setting, yet becomes ineffective in animals selectively deficient for S1P1 on astrocytes, despite maintained normal immunologic receptor expression and functions, and S1P-mediated immune activities. Here we review S1P signaling effects relevant to MS in neural cell types expressing S1P receptors, including astrocytes, oligodendrocytes, neurons, microglia and dendritic cells. The direct effects of fingolimod on these CNS cells observed in preclinical studies are discussed in view of the functional consequences of reducing neurodegenerative processes and promoting myelin preservation and repair. The therapeutic implications of S1P modulation in the CNS are considered in terms of the clinical outcomes of MS, such as reducing MS-related brain atrophy, and other CNS disorders. Additionally, we briefly outline other existing and investigational MS therapies that may also have effects in the CNS.
.jpg)
