Research

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Maria K.  Lehtinen, PhD

Maria Lehtinen, PhD
Program:
Neurobiology Program
Department:
Pathology Research
Hospital Title:
Research Associate
Academic Title:
Assistant Professor of Pathology, Harvard Medical School
Research Focus Area:
Cerebrospinal fluid-based signaling in the nervous system
Contact:
617-919-3504
Contact Via Email
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Research Overview

Our ultimate goal is to understand how the cerebrospinal fluid provides an adaptive and instructive signaling niche for the developing, adult, and aging brain.The neural precursor cells that build the developing brain are remarkably synchronized, yet no central command coordinating this process has been identified. Neural precursors divide immediately adjacent to cerebrospinal fluid (CSF)-filled ventricles and extend primary cilia into the CSF, suggesting that the cerebrospinal fluid may play an important role in instructing brain development. Our research recently revealed that the CSF proteome is both elaborate and dynamic, and that in addition to its passive role as a fluid cushion for the brain, the CSF actively provides a rich and adaptive library of secreted factors that help coordinate neurogenesis.

We found that during embryonic brain development, secreted factors in the CSF bind to receptors located along the apical, ventricular surface of progenitor cells, thus providing instructive cues that activate signaling pathways in these cells. Many signals in the CSF demonstrate age-dependence. For example, the expression of Igf2 in CSF peaks during embryonic brain development, during which it binds to its receptors located on the surface of neural precursor cells and instructs neural precursors to divide. Much of the proliferative effect of CSF is attributable to Igf2, but the CSF is a rich source other signaling activities as well. The ability of secreted factors in the CSF to stimulate signaling in precursors relies on appropriately positioned signaling machinery at the ventricular surface, underscoring the importance of precursor cell polarity and the integration of cell-intrinsic and cell-extrinsic signaling during brain development. Our findings raise many exciting questions about the brain-CSF interface. We are employing diverse experimental approaches that draw on molecular neuroscience, developmental neurobiology, biochemistry, and genetics to investigate:

  • Active feedback regulation of the CSF environment 
  • Precursor cell polarity and sensing of CSF by primary cilia
  • CSF signaling in neuropathological conditions

About Maria Lehtinen

Maria Lehtinen received her Ph.D. in Neurobiology from Harvard University, where she trained with Azad Bonni on signaling mechanisms that regulate neuronal survival and death. She joined Anna-Elina Lehesjoki’s lab for her first postdoc at the University of Helsinki where she investigated the role of redox homeostasis in progressive myoclonus epilepsy. She then carried out a second postdoc with Christopher A. Walsh at Children’s Hospital where she discovered that secreted factors in the cerebrospinal fluid (CSF) play an active role in instructing the development of the mammalian cerebral cortex. The Lehtinen lab carries out basic and translational research on CSF-based signaling. She has been supported by the NIH, NSF, Ellison/AFAR, and the Sigrid Juselius Foundation, and is currently an Alfred P. Sloan Research Fellow.

Publications

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  1. Crespel A, Ferlazzo E, Franceschetti S, Genton P, Gouider R, Kälviäinen R, Korja M, Lehtinen MK, Mervaala E, Simonato M, Vaarmann A. Unverricht-Lundborg disease. Epileptic Disord. 2016 Sep 1; 18(S2):28-37.
  2. Mathew RS, Mullan H, Blusztajn JK, Lehtinen MK. Comment on "Multiple repressive mechanisms in the hippocampus during memory formation". Science. 2016 Jul 29; 353(6298):453.
  3. Terauchi A, Johnson-Venkatesh EM, Bullock B, Lehtinen MK, Umemori H. Retrograde fibroblast growth factor 22 (FGF22) signaling regulates insulin-like growth factor 2 (IGF2) expression for activity-dependent synapse stabilization in the mammalian brain. Elife. 2016 Apr 15; 5.
  4. Chau KF, Springel MW, Broadbelt KG, Park HY, Topal S, Lun MP, Mullan H, Maynard T, Steen H, LaMantia AS, Lehtinen MK. Progressive Differentiation and Instructive Capacities of Amniotic Fluid and Cerebrospinal Fluid Proteomes following Neural Tube Closure. Dev Cell. 2015 Dec 21; 35(6):789-802.
  5. Lun MP, Monuki ES, Lehtinen MK. Development and functions of the choroid plexus-cerebrospinal fluid system. Nat Rev Neurosci. 2015 Aug; 16(8):445-57.
  6. Chang JT, Lehtinen MK, Sive H. Zebrafish cerebrospinal fluid mediates cell survival through a retinoid signaling pathway. Dev Neurobiol. 2016 Jan; 76(1):75-92.
  7. Lehtinen MK, Bjornsson CS, Dymecki SM, Gilbertson RJ, Holtzman DM, Monuki ES. The choroid plexus and cerebrospinal fluid: emerging roles in development, disease, and therapy. J Neurosci. 2013 Nov 6; 33(45):17553-9.
  8. Zappaterra MW, LaMantia AS, Walsh CA, Lehtinen MK. Isolation of cerebrospinal fluid from rodent embryos for use with dissected cerebral cortical explants. J Vis Exp. 2013 Mar 11; (73):e50333.
  9. Lehtinen MK. Adult neurogenesis: VCAM stems the tide. Cell Stem Cell. 2012 Aug 3; 11(2):137-8.
  10. Zappaterra MW, Lehtinen MK. The cerebrospinal fluid: regulator of neurogenesis, behavior, and beyond. Cell Mol Life Sci. 2012 Sep; 69(17):2863-78.
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  12. Lehtinen MK, Walsh CA. Neurogenesis at the brain-cerebrospinal fluid interface. Annu Rev Cell Dev Biol. 2011; 27:653-79.
  13. Tucker ES, Lehtinen MK, Maynard T, Zirlinger M, Dulac C, Rawson N, Pevny L, Lamantia AS. Proliferative and transcriptional identity of distinct classes of neural precursors in the mammalian olfactory epithelium. Development. 2010 Aug 1; 137(15):2471-81.
  14. Lehtinen MK, Bonni A. Demystifying MST family kinases in cell death. Curr Mol Med. 2008 Jun; 8(4):313-8.
  15. Lehtinen MK, Bonni A. Modeling oxidative stress in the central nervous system. Curr Mol Med. 2006 Dec; 6(8):871-81.
  16. Lehtinen MK, Yuan Z, Boag PR, Yang Y, Villén J, Becker EB, DiBacco S, de la Iglesia N, Gygi S, Blackwell TK, Bonni A. A conserved MST-FOXO signaling pathway mediates oxidative-stress responses and extends life span. Cell. 2006 Jun 2; 125(5):987-1001.
  17. Benedito AB, Lehtinen M, Massol R, Lopes UG, Kirchhausen T, Rao A, Bonni A. The transcription factor NFAT3 mediates neuronal survival. J Biol Chem. 2005 Jan 28; 280(4):2818-25.
  18. Shalizi A, Lehtinen M, Gaudilliere B, Donovan N, Han J, Konishi Y, Bonni A. Characterization of a neurotrophin signaling mechanism that mediates neuron survival in a temporally specific pattern. J Neurosci. 2003 Aug 13; 23(19):7326-36.
  19. Konishi Y, Lehtinen M, Donovan N, Bonni A. Cdc2 phosphorylation of BAD links the cell cycle to the cell death machinery. Mol Cell. 2002 May; 9(5):1005-16.
  20. Wiemelt AP, Lehtinen M, McMorris FA. Agonists calcitonin, corticotropin-releasing hormone, and vasoactive intestinal peptide, but not prostaglandins or beta-adrenergic agonists, elevate cyclic adenosine monophosphate levels in oligodendroglial cells. J Neurosci Res. 2001 Jul 15; 65(2):165-72.
  21. Anttila T, Saikku P, Koskela P, Bloigu A, Dillner J, Ikäheimo I, Jellum E, Lehtinen M, Lenner P, Hakulinen T, Närvänen A, Pukkala E, Thoresen S, Youngman L, Paavonen J. Serotypes of Chlamydia trachomatis and risk for development of cervical squamous cell carcinoma. JAMA. 2001 Jan 3; 285(1):47-51.
  22. Paavonen J, Halttunen M, Hansson BG, Nieminen P, Rostila T, Lehtinen M. Prerequisites for human papillomavirus vaccine trial: results of feasibility studies. J Clin Virol. 2000 Oct; 19(1-2):25-30.
  23. Kim S, Lehtinen MK, Sessa A, Zappaterra MW, Cho SH, Gonzalez D, Boggan B, Austin CA, Wijnholds J, Gambello MJ, Malicki J, LaMantia AS, Broccoli V, Walsh CA. The apical complex couples cell fate and cell survival to cerebral cortical development. Neuron. 2010 Apr 15; 66(1):69-84.
  24. Lehtinen MK, Zappaterra MW, Chen X, Yang YJ, Hill AD, Lun M, Maynard T, Gonzalez D, Kim S, Ye P, D'Ercole AJ, Wong ET, LaMantia AS, Walsh CA. The cerebrospinal fluid provides a proliferative niche for neural progenitor cells. Neuron. 2011 Mar 10; 69(5):893-905.
  25. Yuan Z, Lehtinen MK, Merlo P, Villén J, Gygi S, Bonni A. Regulation of neuronal cell death by MST1-FOXO1 signaling. J Biol Chem. 2009 Apr 24; 284(17):11285-92.
  26. Lehtinen MK, Tegelberg S, Schipper H, Su H, Zukor H, Manninen O, Kopra O, Joensuu T, Hakala P, Bonni A, Lehesjoki AE. Cystatin B deficiency sensitizes neurons to oxidative stress in progressive myoclonus epilepsy, EPM1. J Neurosci. 2009 May 6; 29(18):5910-5.
  27. Poduri A, Evrony GD, Cai X, Elhosary PC, Beroukhim R, Lehtinen MK, Hills LB, Heinzen EL, Hill A, Hill RS, Barry BJ, Bourgeois BF, Riviello JJ, Barkovich AJ, Black PM, Ligon KL, Walsh CA. Somatic activation of AKT3 causes hemispheric developmental brain malformations. Neuron. 2012 Apr 12; 74(1):41-8.
  28. Lun MP, Johnson MB, Broadbelt KG, Watanabe M, Kang YJ, Chau KF, Springel MW, Malesz A, Sousa AM, Pletikos M, Adelita T, Adelita T, Calicchio ML, Zhang Y, Holtzman MJ, Lidov HG, Sestan N, Steen H, Monuki ES, Lehtinen MK. Spatially heterogeneous choroid plexus transcriptomes encode positional identity and contribute to regional CSF production. J Neurosci. 2015 Mar 25; 35(12):4903-16.
  29. Zhou G, Hotta J, Lehtinen MK, Forss N, Hari R. Enlargement of choroid plexus in complex regional pain syndrome. Sci Rep. 2015 Sep 21; 5:14329.
  30. Li L, Grausam KB, Wang J, Lun MP, Ohli J, Lidov HG, Calicchio ML, Zeng E, Salisbury JL, Wechsler-Reya RJ, Lehtinen MK, Schüller U, Zhao H. Sonic Hedgehog promotes proliferation of Notch-dependent monociliated choroid plexus tumour cells. Nat Cell Biol. 2016 Apr; 18(4):418-30.
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