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Lori J Lorenz PhD

TitleAssistant Professor
InstitutionUniversity of Massachusetts Medical School
DepartmentProgram in Molecular Medicine
Phone508-856-2288
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    Other Positions
    InstitutionUMMS - School of Medicine
    DepartmentNeuroNexus Institute

    InstitutionUMMS - School of Medicine
    DepartmentProgram in Molecular Medicine


    Collapse Biography 
    Collapse education and training
    Purdue University West Lafayette, West Lafayette, IN, United StatesBSBiochemistry & Molecular Bio
    Brandeis University, Waltham, MA, United StatesPHDMolecular Neurobiology

    Collapse Overview 
    Collapse overview


    My interests are in the brain and in genes that control neural function and behavior. 



    I received a BS degree in Biochemistry and Molecular Biology at Purdue University while studying neuropeptide synthesis with Jack Dixon (Magazin et al.,1982; Deschenes et al., 1984), and then earned a PhD in Biology with an NIH predoctoral fellowship to study circadian rhythms with Michael Rosbash at Brandeis University. The idea of controlling behavior in an organism by gene transformation was both radical and exciting. The Rosbash and Young groups identified period (per) gene function in circadian rhythms in Drosophila. I found by RNA in situ hybridization that per was expressed in several tissues, and in embryos, suggesting widespread clock gene activity (Liu et al., 1988); I also found that a neighboring transcript involved in eclosion was under control of the circadian clock in pupae (Lorenz et al., 1989). I further discovered that per mRNA levels cycle in adult flies in light:dark conditions, suggesting a transcriptional role in the generation of rhythms (Hardin et al., 1990). 



    I studied with Norbert Perrimon at Harvard Medical School with NIH postdoctoral funding, while the GAL4/UAS transgene expression system was being developed. As postocs, Dan Eberl and I identified roles for an RNA helicase in embryonic development and somatic heterochromatin formation (Eberl et al., 1997). We also collaborated on a calcium channel gene in Drosophila (Eberl et al., 1998). I focused on neurodevelopment as an Instructor with David Van Vactor (Van Vactor and Lorenz, 1999) and a Taplin Foundation Award. In 2002, I came to the University of Massachusetts Medical School with a grant from the Whitehall Foundation to collaborate with Joel Richter on translation in the nervous system as an Assistant Professor of Molecular Medicine.



    The Richter lab identified the RNA-binding protein, CPEB, as an activator of mRNA translation in early development in frogs and mice. CPEB also was expressed in brain, and we found it affected experience-dependent translation (Wu et al., 1998). We realized that mechanisms of localized translation in early development might control neuronal activity and/or development at adult synapses to regulate higher cognitive functions. (Richter and Lorenz, 2002). Subsequent studies in the Richter lab confirmed a role for CPEB in plasticity (Alarcon et al., 2004) and in memory (Berger-Sweeney et al., 2006).



    At Harvard, I discovered a gene in Drosophila that encodes a protein with motifs conserved in mice and humans resembling those in proteins that bind the eIF4E initiation factor to inhibit cap-dependent mRNA translation. The Richter lab and I demonstrated that the protein, which we call Neuroguidin, is, in fact, an eIF4E-binding protein. We further found that Neuroguidin interacts with CPEB and preferentially inhibits translation through a cytoplasmic polyadenylation element-binding site for CPEB (Jung et al., 2006). We then showed that Neuroguidin regulates mRNA translation and synaptic plasticity in the rodent brain (Udagawa et al., 2012). 



    Basic research using model organisms reveal molecular pathways that underlie human disease. We often focus on mice, though flies, like humans, sleep at night and thus, may be superior models for certain types of behavioral research. Gene duplication, though increasing viability, can complicate functional studies in higher organisms. By studying single homologs in flies, we may better understand molecular pathways driving neurological disorders in humans. 



    Consider: Drosophila locomotor activity patterns entrain to light/dark environments similarly to humans, reflecting high activity during the day (especially morning and early evening) and reduced levels (sleep) at night. Using transgenic P-element, GAL4/UAS and RNAi techniques, we have found that homologs of Neuroguidin and CPEB (Orb) control rest/activity patterns in light/dark conditions, suggesting a role for regulated translation in the generation of sleep/wake behavior. Neuronal knockdown of Orb2, a member of the CPEB family, impairs locomotor activity in flies, suggesting a role in arousal and/or motor functions. 



    Hyperexcitability is common in autistic individuals upon silencing of the fragile X mental retardation gene, fmr1. Ovarian germ cell defects due to loss of dfmr in flies is rescued by reduced Orb (Costa et al., 2005). We wondered whether reduced CPEB could rescue defects in a mouse model of fragile X syndrome, and found that it does, indeed, rescue electrophysiologic, developmental, and behavioral defects in fmrp-mutant mice (Udagawa et al., 2013). Knockdown of dfmr in flies results in hyper-excitable adults. Identification of molecular targets and neuronal circuits controlling excitability in model organisms may reveal how CPEB and FMRP interact to control complex behaviors.



    Much of what we have learned about genetic and molecular controls of protein synthesis was discovered in simple organisms. Much of what we infer to be happening in the brain, controlled by these same genes, comes from humble origins. Research with flies has lead to important ideas and discoveries in mice and humans. With NIH and private funding, we hope to further develop our studies with small, though powerful, brains.



     





     



    Involvement of CPEB in mediating FMRP activity



    Cytoplasmic polyadenylation element-binding protein (CPEB) associates with CPEs in the 3′ untranslated region (UTR) of target mRNAs and stimulates translation by promoting lengthening of the poly(A) tail. Neuroguidin is a eukaryotic initiation factor 4E (eIF4E)-binding protein (4E-BP) that binds to CPEB to prevent CPE-dependent translation. Excessive translation in fragile X syndrome (FXS) model mice is normalized by genetic reduction of CPEB, although the mechanisms through which the two proteins interact are currently unclear.



    Copied with Permission from:



    Nat Rev Neurosci. 2015 Oct; 16(10): 595–605.



    Dysregulation and restoration of translational homeostasis in fragile X syndrome



    Joel D. Richter,1 Gary J. Bassell,2 and Eric Klann3



    Collapse Post Docs


    Mi-Young Jung, a former postdoc, generated the first photographs of Neuroguidin particles in growth cones and axons of cultured rat hippocampal neurons. Tsuyoshi Udagawa demonstrated a role for Neuroguidin in synaptic plasticity by knocking it down in the adult rat brain. He also lead experiments to rescue autistic behaviors in fragile X model mice by depletion of CPEB. Fernanda Mansur is investigating effects of Neuroguidin and other CPEB-interacting proteins on mouse behavior. Discovering molecular and cellular mechanisms by which FMRP and CPEB interact to control neuronal function and behavior is of major interest in our laboratory. 



     



                                               



     




    Collapse Bibliographic 
    Collapse selected publications
    Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
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    1. Udagawa T, Farny NG, Jakovcevski M, Kaphzan H, Alarcon JM, Anilkumar S, Ivshina M, Hurt JA, Nagaoka K, Nalavadi VC, Lorenz LJ, Bassell GJ, Akbarian S, Chattarji S, Klann E, Richter JD. Genetic and acute CPEB1 depletion ameliorate fragile X pathophysiology. Nat Med. 2013 Nov; 19(11):1473-7. PMID: 24141422.
      View in: PubMed
    2. Udagawa T, Swanger SA, Takeuchi K, Kim JH, Nalavadi V, Shin J, Lorenz LJ, Zukin RS, Bassell GJ, Richter JD. Bidirectional control of mRNA translation and synaptic plasticity by the cytoplasmic polyadenylation complex. Mol Cell. 2012 Jul 27; 47(2):253-66. PMID: 22727665.
      View in: PubMed
    3. Jung MY, Lorenz L, Richter JD. Translational control by neuroguidin, a eukaryotic initiation factor 4E and CPEB binding protein. Mol Cell Biol. 2006 Jun; 26(11):4277-87. PMID: 16705177.
      View in: PubMed
    4. Richter JD, Lorenz LJ. Selective translation of mRNAs at synapses. Curr Opin Neurobiol. 2002 Jun; 12(3):300-4. PMID: 12049937.
      View in: PubMed
    5. Van Vactor D, Lorenz LJ. Introduction: invertebrate axons find their way. Cell Mol Life Sci. 1999 Aug 30; 55(11):1355-7. PMID: 10518985.
      View in: PubMed
    6. Van Vactor DV, Lorenz LJ. Neural development: The semantics of axon guidance. Curr Biol. 1999 Mar 25; 9(6):R201-4. PMID: 10209089.
      View in: PubMed
    7. Eberl DF, Ren D, Feng G, Lorenz LJ, Van Vactor D, Hall LM. Genetic and developmental characterization of Dmca1D, a calcium channel alpha1 subunit gene in Drosophila melanogaster. Genetics. 1998 Mar; 148(3):1159-69. PMID: 9539432.
      View in: PubMed
    8. Eberl DF, Lorenz LJ, Melnick MB, Sood V, Lasko P, Perrimon N. A new enhancer of position-effect variegation in Drosophila melanogaster encodes a putative RNA helicase that binds chromosomes and is regulated by the cell cycle. Genetics. 1997 Jul; 146(3):951-63. PMID: 9215899.
      View in: PubMed
    9. Lorenz LJ, Hall JC, Rosbash M. Expression of a Drosophila mRNA is under circadian clock control during pupation. Development. 1989 Dec; 107(4):869-80. PMID: 2517256.
      View in: PubMed
    10. Liu X, Lorenz L, Yu QN, Hall JC, Rosbash M. Spatial and temporal expression of the period gene in Drosophila melanogaster. Genes Dev. 1988 Feb; 2(2):228-38. PMID: 3129339.
      View in: PubMed
    11. Lorenz LJ, Richter JD. A cDNA clone for a polyadenylated RNA-binding protein of Xenopus laevis oocytes hybridizes to four developmentally regulated mRNAs. Mol Cell Biol. 1985 Oct; 5(10):2697-704. PMID: 3915533.
      View in: PubMed
    12. Richter JD, Lorenz LJ, Audet RG. Membrane-bound mRNAs are recruited from preinitiated ribonucleoprotein particles in injected Xenopus oocytes. J Biol Chem. 1985 Apr 10; 260(7):4448-54. PMID: 3884610.
      View in: PubMed
    13. Deschenes RJ, Lorenz LJ, Haun RS, Roos BA, Collier KJ, Dixon JE. Cloning and sequence analysis of a cDNA encoding rat preprocholecystokinin. Proc Natl Acad Sci U S A. 1984 Feb; 81(3):726-30. PMID: 6199787.
      View in: PubMed
    14. Dixon JE, Andrews PC, Collier K, Deschenes R, Funckes C, Lorenz L, Magazin M, Minth CD, Nichols R, Tavianini M, et al. Cloning and biosynthetic studies of rat somatostatin. Scand J Gastroenterol Suppl. 1983; 82:25-31. PMID: 6138851.
      View in: PubMed
    15. Markow, T.A., Richmond, R.C., Mueller, L., Sheer, I., Roman, S., Laetz, C. and Lorenz, L. Testing for rare male mating advantages among various strains of Drosophila melanogaster. Genetical Research. 1980; (35):59-64.
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