prof. dr. M.P. (Marten) Smidt


  • Faculty of Science
    SILS
  • POSTBUS  94232
    1090 GE  Amsterdam
    Room number: C4.102
  • M.P.Smidt@uva.nl
    T:  0205256479

 

 

Within the MartenSmidtLab we work on fundamental processes of brain development and use that framework to understand mechanisms of pathology. 

 

 

 

 

Development of the mdDA neuronal pool (Red) in a coronal plane with radial glia (Green)

Current research lines:

  1. Influence of neurotransmitters on neuronal development. 
  2. Role of FoxO6 in Cortical development 
  3. Role of FoxO proteins in regulating the circadian clock 
  4. Development of the mesodiencephalic dopaminergic system
  5. Epigenetic regulation of neuronal development
  6. Molecular evolution of the human cortex 

 

 

Research background

My main interest is molecular programming during development of the central nervous system. Since at that time almost nothing was known on the subject, I started with JPH Burbach a cloning effort to identify transcription factors that play a role during CNS development. From this work three major breakthroughs were established:
1. The cloning, identification and characterization of the homeobox gene Pitx3 [Smidt MP pnas 1997]. This gene was found to beexclusively expressed in the substantia nigra (SNc) and ventral tegmental area (VTA) forming the midbrain dopamine system, essential for mood and movement regulation in mammals. The real impact of the work was that this factor is exclusively expressed in these neurons and this formed the first step in the understanding of molecular programming of midbrain dopamine neurons.
2. The identification of the role of the orphan nuclear hormone receptor Nurr1  [Saucedo-Cardenas pnas 1998]. It was shown by us and others that Nurr1 is essential for the development of fully differentiated midbrain dopamine neurons. This was the second factor identified to be involved in midbrain dopamine neurodevelopment.
3. The identification of Lmx1b (publication [Smidt MP nat-neurosc.-2000]. We showed that the early specification of the midbrain by Lmx1b is essential for the formation of midbrain dopaminergic neurons. Moreover, we showed that TH expression was possible in early DA neurons without the expression of Pitx3, indicating that Pitx3 might be involved in molecular processes other than transmitter phenotype. 
After this cloning and descriptive phase I was interested to go into depth into the role of Pitx3 (as an NWO fellow) in the neurodevelopment of midbrain dopamine neurons and to broaden my view on molecular signaling events in neuronal cells. This was accomplished by the start of analysis of the Pitx3 knock out and by the start of a new research line on forkhead proteins (FoxO and FoxK family). The work lead to three major findings:
1. The data from the Pitx3 knock-out analysis (aphakia mouse) formed anew chapter in the understanding of the role of Pitx3 in the development of midbrain dopamine neurons (publication [enu:Smidt-MP development-2004]). We showed that Pitx3 is essential for the formation of the SNc and the ventral part of the VTA. Moreover it was clear from the analysis that the defect was apparent at the early stage of terminal differentiation, Most importantly, the defect was not present in all midbrain dopamine neurons but mainly in the ventral medial SNc and ventral VTA.
2. The cloning and functional characterization of FoxO6, a novel member of the FoxO family (FoxO1, FoxO3 and FoxO4). We showed that FoxO6 had unique properties in terms of nucleo-cytoplasmic shuttling, as a result of PKB signaling, compared to its family members  [Jacobs FM jbc2003]. Later we showed the mechanism of the altered shuttling behavior and showed that phosphorylation by PKB does inactivate FoxO6 by inhibiting DNA interaction without the extra level of inhibition of nuclear removal (publication [enu:van-der-Heide BJ 2005]). We have gained quickly a good position by this work. A review from our team received much enthusiasm as highlighted by 82 citations so-far and the 25th place of most downloaded papers in the publication year [Van-Der-Heide BJ review 2004].
3. The identification a novel factor of the FoxK family, namely (mouse) Foxk2. This factor was, based on sequence homology, the designated orthologue of yeast Fkh2 which is essential in the progression of the cell-cycle (G2/M phase progression). Our analysis showed that the functional similarity is not apparent, Foxk2 has a function in cell-survival but does not stimulate the G2/M phase transition.
The fact that a subset of the complete group of dopamine neurons was affected in the Pitx3 knock-out (Pitx3 itself is expressed in all midbrain dopamine cells) initiated the novel idea that the molecular coding of the SNc and VTA is not the same. A real step forward was madeby the identification of subset specific markers and coding differences in the ventricular zone. This concept of subset specification was a crucial step in the way the field regarded the molecular pathways leading to the development of dopamine neurons of the SNc and VTA [Smits SM prog neurobiol-2006]. In addition, it became clear that the neurons populating the SNc and VTA are not generated exclusively in the midbrain but also in the diencephalon. Therefore, the name of this neuronal group was changed to mesodiencephalic dopaminergic (mdDA) neurons and has been used as such from that point on.
This was a crucial moment in my career, i established my own group and my work clearly surpassed the initial identification and function-description of transcription factors involved in the development of mdDA neurons. My interest went into two additionally research directions:
1. The live visualization of dopamine neurotransmission through multi-pinhole SPECT. Prof dr. Freek Beekman designed a spectacular micro-SPECT system to follow tracers in the mouse brain with a resolution of 0.3 mm. Together we started to image live dopamine transmitter events in a living mouse. This work has lead to two high impact publications [Beekman FJ nucl medicin 2005] and [Vastenhouw B mol psych 2007]. 
2. Understand how subset specification is established, which subsets exist and what the relationship is between subset and specific connectivity. A crucial finding in the understanding of subsets specific molecular coding was established through the identification of a subset specific transcriptional target of Pitx3. This gene, (retinal) aldehyde dehydrogenase 2 (Ahd2, Raldh1) is expressed, in the adult brain, in the ventral cells of the SNc and VTA, the neurons that are lost in the Pitx3 mutant  [Jacobs FM development 2007]. A second novel finding was that retinoic acid (RA) has a role in terminal differentiation of this specific set of neurons in addition to its role in the ventricularzone. Ahd2 is present in ventricular zone cells, its transcription is terminated when cells leave the ventricular zone and under the control of Pitx3, Ahd2 is transcribed again in a (lateral) subset of mdDA neurons and is essential for the synthesis of RA out of retinal. We were able to show the dependence of mdDA differentiation for RA signalling by rescuing the Pitx3 knock-out phenotype through the exogenous application of RA. 
Although I am still working on- and interested in the FoxO6 knock out (we have generated chimeric animals) my main interest lies with the molecular programming of mdDA neuronal subsets. My lab is currently investigating 1) why Ahd2 activation is only happening in the described subset; 2) we are mapping transcriptional targets of Engrailed, Lmx1a/b, and Nurr1 to get a better idea about the molecular programming that is initiated within mdDA neurons; 3) the functional interaction between Pitx3/Nurr1 and En1 and 4) we are finalizing the identification of adult subset specific markers. At this moment my research group consist of 3 PhD students, 2 technicians and every year about 3 master students.
The work described above has been very fruit-full and has lead to a leading position of my research group mainly in the field of development and engineering of mdDA neurons, marked by many invitations to write reviews/books on the topic, the high amount of peer-reviewed publications and the invitations to speak at the international level about my work.
Recently, I have initiated a European collaboration called mdDANeurodev (see www.mdDAneurodev.eu) which was funded in the KP7 scheme (2008) and in addition i was awarded a VICI grant from NWO-ALW (2008/2009).

Publications

  • Oostland M, Buijink MR, Teunisse GM, von Oerthel L, Smidt MP, van Hooft JA. Distinct Temporal Expression of 5-HT1A and 5-HT 2A Receptors on Cerebellar Granule Cells in Mice. Cerebellum. 2014 May 1. [Epub ahead of print] PMID: 24788088 [PubMed - as supplied by publisher] 
  • Roessler R, Smallwood SA, Veenvliet JV, Pechlivanoglou P, Peng SP, Chakrabarty K, Groot-Koerkamp MJ, Pasterkamp RJ, Wesseling E, Kelsey G, Boddeke E, Smidt MP, Copray S. Detailed Analysis of the Genetic and Epigenetic Signatures of iPSC-Derived Mesodiencephalic Dopaminergic Neurons. Stem Cell Reports. 2014 Apr 3;2(4):520-33. doi: 10.1016/j.stemcr.2014.03.001. eCollection 2014 Apr 8. PMID: 24749075 [PubMed] Free PMC Article
  • Smidt MP, van Hooft JA. Subset specification of central serotonergic neurons. Front Cell Neurosci. 2013 Oct 31;7:200. doi: 10.3389/fncel.2013.00200. Review. PMID: 24198761 [PubMed] Free PMC Article
  • Smits SM, von Oerthel L, Hoekstra EJ, Burbach JP, Smidt MP. Molecular marker differences relate to developmental position and subsets of mesodiencephalic dopaminergic neurons. PLoS One. 2013 Oct 7;8(10):e76037. doi: 10.1371/journal.pone.0076037. ECollection 2013. PMID: 24116087 [PubMed - in process] Free PMC Article
  • Hoekstra EJ, von Oerthel L, van der Heide LP, Kouwenhoven WM, Veenvliet JV, Wever I, Jin YR, Yoon JK, van der Linden AJ, Holstege FC, Groot Koerkamp MJ, Smidt MP. (2013)  Lmx1a Encodes a Rostral Set of Mesodiencephalic Dopaminergic Neurons Marked by the Wnt/B-Catenin Signaling Activator R-spondin 2. PLoS One. 2013 Sep 16;8(9):e74049. doi: 10.1371/journal.pone.0074049.
  • Jesse V Veenvliet*, Maria TM Alves dos Santos*, Willemieke M Kouwenhoven, Lars von Oerthel, Jamie L Lim, Annemarie JA van der Linden, Marian JA Groot Koerkamp, Frank CP Holstege and Marten P Smidt (2013) En1 and Pitx3 interplay in dopaminergic subset-specification. Development 140, 3373-3384 (2013) doi:10.1242/dev.094565 IP7 * shared first authorship
  • Mareen Engel, Marten P Smidt*, Johannes A Van Hooft* (2013) The serotonin 5-HT3 receptor: a novel neurodevelopmental target. Front Cell Neurosci. 2013;7:76. doi: 10.3389/fncel.2013.00076. . Shared last author
  • Lars P. van der Heide and Marten P. Smidt (2013) The BCL2-code to dopaminergic development and Parkinson's disease. Trends Mol Med. 19(4):211-6. 
  • van Heesbeen HJ, Mesman S, Veenvliet JV, Smidt MP. (2013) Epigenetic mechanisms in the development and maintenance of dopaminergic neurons. Development. 2013 Mar;140(6):1159-69. doi: 10.1242/dev.089359. 
  • Nott A, Nitarska J, Veenvliet JV, Schacke S, Derijck AA, Sirko P, Muchardt C, Pasterkamp RJ, Smidt MP, Riccio A. (2013) S-nitrosylation of HDAC2 regulates the expression of the chromatin-remodeling factor Brm during radial neuron migration. Proc Natl Acad Sci U S A. 110(8):3113-8. 
  • Hoekstra EJ, Mesman S, de Munnik WA, Smidt MP. (2013) Lmx1b Is Part of a Transcriptional Complex with PSPC1 and PSF. PLoS One. 2013;8(1):e53122. doi: 10.1371/journal.pone.0053122. Epub 2013 Jan 4. I
  • Hoekstra EJ, von Oerthel L, van der Linden AJ, Smidt MP. (2012) Phox2b influences the development of a caudal dopaminergic subset. PLoS One. 2012;7(12):e52118. doi: 10.1371/journal.pone.0052118. Epub 2012 Dec 14.
  • Elisa J Hoekstra, Lars von Oerthel, Annemarie J A van der Linden, Raymond D Schellevis, Gerard Scheppink, Frank C.P. Holstege, Marian J Groot-Koerkamp, Lars P van der Heide2, Marten P Smidt (2012) Lmx1a is an activator of Rgs4 and Gbr10 and is responsible for the correct specification of rostral and medial mdDA neurons. Eur J Neurosci. 2012 Oct 29. doi: 10.1111/ejn.12022. 
  • Frank Meye, Ruud van Zessen, Marten Smidt, Roger Adan, and Geert Ramakers (2012) Morphine withdrawal enhances constitutive mu-opioid receptor activity in the ventral tegmental area. J Neurosci. 32(46):16120-8. doi: 10.1523/JNEUROSCI.1572-12.2012. 
  • Smidt MP, von Oerthel L, Hoekstra EJ, Schellevis RD, Hoekman MFM (2012) Spatial and Temporal Lineage Analysis of a Pitx3-Driven Cre-Recombinase Knock-In Mouse Model. PLoS ONE 7(8): e42641. doi:10.1371/journal.pone.0042641
  • Koushik Chakrabarty, Lars von oerthel, Anita Hellemons, M. frederic Clotman, Marian J.A. Groot Koerkamp, Frank C.P. Holstege, R. Jeroen Pasterkamp, and Marten P. Smidt (2012) Genome wide expression profiling of the mesodiencephalic region identifies novel factors involved in early and late dopaminergic development. Biology Open 1:693-704.
  • Laura A. Smit-Rigtera, Cornelle W. Noorlander, Lars von Oerthelb, Pascal Chameau, Marten P. Smidt*, Johannes A. van Hooft* (2012) Prenatal fluoxetine exposure induces life-long serotonin 5-HT3 receptor-dependent cortical abnormalities and anxiety-like behaviour Neuropharmacology Volume 62, Issue 2: 865–870 * Shared last author
  • Jacobs FM, Veenvliet JV, Almirza WH, Hoekstra EJ, von Oerthel L, van der Linden AJ, Neijts R, Koerkamp MG, van Leenen D, Holstege FC, BurbachJP,Smidt MP. Retinoic acid-dependent and -independent gene-regulatory pathways of Pitx3 in meso-diencephalic dopaminergic neurons. Development. 2011 Dec;138(23):5213-22. PubMed PMID: 22069189.
  • Smit-Rigter LA, Noorlander CW, von Oerthel L, Chameau P, Smidt MP, van Hooft JA. Prenatal fluoxetine exposure induces life-long serotonin 5-HT₃ receptor-dependent cortical abnormalitiesandanxiety-like behaviour. Neuropharmacology.2012 Feb;62(2):865-70. Epub 2011 Sep 24. PubMed PMID: 21964434.
  • Alves dos Santos MT, Smidt MP. En1 and Wnt signaling in midbrain dopaminergic  neuronal development. Neural Dev. 2011 May 10;6:23. Review. PubMed PMID: 21569278; PubMed Central PMCID: PMC3104484.
  • Rosemann M, Ivashkevich A, Favor J, Dalke C, Hölter SM, Becker L, Rácz I, Bolle I, Klempt M, Rathkolb B, Kalaydjiev S, Adler T, Aguilar A, Hans W, Horsch M, Rozman J, Calzada-Wack J, Kunder S, Naton B, Gailus-Durner V, Fuchs H, Schulz  H, Beckers J, Busch DH, Burbach JP, Smidt MP, Quintanilla-Martinez L, Esposito I, Klopstock T, Klingenspor M, Ollert M, Wolf E, Wurst W, Zimmer A, de Angelis MH, Atkinson M, Heinzmann U, Graw J. Microphthalmia, parkinsonism, and enhanced nociception in Pitx3 ( 416insG ) mice. Mamm Genome. 2010 Feb;21(1-2):13-27. Epub  2009 Dec 22. PubMed PMID: 20033184.
  • Kolk SM, Gunput RA, Tran TS, van den Heuvel DM, Prasad AA, Hellemons AJ, Adolfs Y, Ginty DD, Kolodkin AL, Burbach JP, Smidt MP, Pasterkamp RJ. Semaphorin  3F is a bifunctional guidance cue for dopaminergic axons and controls their fasciculation, channeling, rostral growth, and intracortical targeting. J Neurosci. 2009 Oct 7;29(40):12542-57. PubMed PMID: 19812329; PubMed Central PMCID: PMC3097132.
  • Smidt MP, Burbach JP. Terminal differentiation ofmesodiencephalic dopaminergic neurons: the role of Nurr1 andPitx3. Adv Exp Med Biol. 2009;651:47-57. Review. PubMed PMID: 19731549.
  • Pasterkamp RJ, Smidt MP, Burbach JP. Development and engineering of dopamine neurons. Preface. Adv Exp Med Biol. 2009;651:v-vi. PubMed PMID: 19731545.
  • Smidt MP, Burbach JP. A passport to neurotransmitter identity. Genome Biol. 2009;10(7):229. Epub 2009 Jul 1. Review. PubMed PMID: 19591649; PubMed Central PMCID: PMC2728521.
  • Jacobs FM, van der Linden AJ,Wang Y, von Oerthel L, Sul HS, Burbach JP, Smidt MP. Identification of Dlk1, Ptpru and Klhl1 as novel Nurr1 target genes in meso-diencephalic dopamine neurons. Development. 2009 Jul;136(14):2363-73. Epub 2009 Jun 10. PubMed PMID: 19515692; PubMed Central PMCID: PMC3266485.
  • Jacobs FM, van Erp S, van der Linden AJ, von Oerthel L, Burbach JP, Smidt MP. Pitx3 potentiates Nurr1 in dopamine neuron terminal differentiation through release of SMRT-mediated repression. Development. 2009 Feb;136(4):531-40. Epub 2009 Jan 14. PubMed PMID: 19144721.
  • Smidt MP. Specific vulnerability of substantia nigra compacta neurons. J Neural Transm Suppl. 2009;(73):39-47. Review. PubMed PMID: 20411766.
  • Noorlander CW, Ververs FF, Nikkels PG, van Echteld CJ, Visser GH, Smidt MP. Modulation of serotonin transporter function during fetal development causes dilated heart cardiomyopathy and lifelong behavioral abnormalities. PLoS One. 2008 Jul 23;3(7):e2782. Erratum in: PLoS One. 2009;4(9). doi: 10.1371/annotation/71abed9d-9ee9-4be0-a663-0d469750e13a. PubMed PMID: 18716672; PubMed Central PMCID: PMC2518512.
  • Smits SM, Noorlander CW, Kas MJ, Ramakers GM, Smidt MP. Alterations in serotonin signalling are involved in the hyperactivity of Pitx3-deficient mice. Eur J Neurosci. 2008 Jan;27(2):388-95. PubMed PMID: 18215235.
  • Vastenhouw B, van der Have F, van der Linden AJ, von Oerthel L, Booij J,Burbach JP, Smidt MP, Beekman FJ. Moviesofdopamine transporter occupancy with ultra-high resolution focusing pinhole SPECT. Mol Psychiatry. 2007 Nov;12(11):984-7. Epub 2007 Jul 10. PubMed PMID: 17957236.
  • Kas MJ, van der Linden AJ, Oppelaar H, von Oerthel L, Ramakers GM, Smidt MP.  Phenotypic segregation of aphakia and Pitx3-null mutants reveals that Pitx3 deficiency increases consolidation of specific movement components. Behav Brain Res. 2008 Jan25;186(2):208-14. Epub 2007 Aug 31. PubMed PMID: 17919745.
  • Jacobs FM, Smits SM, Noorlander CW, von Oerthel L, van der Linden AJ, Burbach JP, Smidt MP. Retinoic acid counteracts developmental defects in the substantia nigra caused by Pitx3 deficiency. Development. 2007 Jul;134(14):2673-84. PubMed PMID: 17592014.
  • Kramer ER, Aron L, Ramakers GM, Seitz S, Zhuang X, Beyer K, Smidt MP, Klein R. Absence of Ret signaling in mice causes progressive and late degeneration of the nigrostriatal system. PLoS Biol. 2007 Mar;5(3):e39. PubMed PMID: 17298183; PubMed Central PMCID: PMC1808500.
  • Smidt MP, Burbach JP. How to make a mesodiencephalic dopaminergic neuron. Nat Rev Neurosci. 2007 Jan;8(1):21-32. Review. Erratum in: Nat Rev Neurosci. 2007 Feb;8(2):160. PubMed PMID: 17180160.
  • Burbach JP, Smidt MP. Molecular programming of stem cells into mesodiencephalic dopaminergic neurons. Trends Neurosci. 2006 Nov;29(11):601-3. Epub 2006 Oct 9. Review. PubMed PMID: 17030431.
  • Smits SM, Smidt MP. The role of Pitx3 in survival of midbrain dopaminergic neurons. J Neural Transm Suppl. 2006;(70):57-60. Review. PubMed PMID: 17017509.
  • Sgadò P, Albéri L, Gherbassi D, Galasso SL, Ramakers GM, Alavian KN, Smidt MP, Dyck RH, Simon HH. Slow progressive degeneration of nigral dopaminergic neurons in postnatal Engrailed mutant mice. Proc Natl Acad Sci U S A. 2006Oct 10;103(41):15242-7. Epub 2006 Oct2. PubMed PMID: 17015829; PubMed Central PMCID: PMC1622807.
  • van der Heide LP, Ramakers GM, Smidt MP. Insulin signaling in the central nervous system: learning to survive. Prog Neurobiol. 2006 Jul;79(4):205-21. Epub  2006 Aug 17. Review. PubMed PMID: 16916571.
  • de Rover M, Lodder JC, Smidt MP, Brussaard AB. Pitx3 deficiency in mice affectscholinergic modulation of GABAergic synapses in thenucleus accumbens. J  Neurophysiol. 2006 Oct;96(4):2034-41. Epub 2006 Jul 12. PubMed PMID: 16837663.
  • Jacobs FM, Smits SM, Hornman KJ, Burbach JP, Smidt MP. Strategies to unravel  molecular codes essential for the development of meso-diencephalic dopaminergic neurons. J Physiol. 2006 Sep 1;575(Pt 2):397-402. Epub 2006 Jun 29. Review. PubMed PMID: 16809365; PubMed Central PMCID: PMC1819470.
  • Wijchers PJ, Burbach JP, Smidt MP. In control of biology: of mice, men and Foxes. Biochem J. 2006 Jul 15;397(2):233-46. Review. PubMed PMID: 16792526; PubMed Central PMCID: PMC1513289.
  • Asbreuk CH, van Doorninck JH, Mansouri A, Smidt MP, Burbach JP. Neurohypophysial dysmorphogenesis in mice lacking the homeobox gene Uncx4.1. J Mol Endocrinol. 2006 Feb;36(1):65-71. PubMed PMID: 16461927.
  • Smits SM, Burbach JP, Smidt MP. Developmental origin and fate of meso-diencephalic dopamine neurons. Prog Neurobiol. 2006 Jan;78(1):1-16. Epub 2006 Jan 18. Review. PubMed PMID: 16414173.
  • Wijchers PJ, Hoekman MF, Burbach JP, Smidt MP. Identification of forkhead transcription factors in cortical and dopaminergic areas of the adult murine brain. Brain Res. 2006 Jan 12;1068(1):23-33. Epub 2005 Dec 27. PubMed PMID: 16376864.
  • Hoekman MF, Jacobs FM, Smidt MP, Burbach JP. Spatial and temporal expression  of FoxO transcription factors in the developing and adult murine brain. Gene Expr Patterns. 2006 Jan;6(2):134-40. Epub 2005 Dec 2. PubMed PMID: 16326148.
  • Wijchers PJ, Hoekman MF, Burbach JP, Smidt MP. Cloning and analysis of the murine Foxi2 transcription factor. Biochim Biophys Acta. 2005 Nov 10;1731(2):133-8. Epub 2005 Oct 5. PubMed PMID: 16289364.
  • Smits SM, van der Nobelen S, Hornman KJ, von Oerthel L, Burbach JP, Smidt MP. Signalling through phospholipase C beta 4 is not essential formidbrain dopaminergic neuron survival. Neuroscience. 2005;136(1):171-9. Epub 2005 Sep 28.  PubMed PMID: 16198487.
  • Smits SM, Mathon DS, Burbach JP, Ramakers GM, Smidt MP. Molecular and cellular alterations in the Pitx3-deficient midbrain dopaminergic system. Mol Cell Neurosci. 2005 Nov;30(3):352-63. Epub 2005 Sep 6. PubMed PMID: 16140547.
  • Beekman FJ, van der Have F, Vastenhouw B, van der Linden AJ, van Rijk PP, Burbach JP, Smidt MP. U-SPECT-I: a novel system for submillimeter-resolution tomography with radiolabeled molecules in mice. J Nucl Med. 2005 Jul;46(7):1194-200. PubMed PMID: 16000289.
  • van der Heide LP, Jacobs FM, Burbach JP, Hoekman MF, Smidt MP. FoxO6 transcriptional activity is regulated by Thr26 and Ser184, independent of nucleo-cytoplasmic shuttling. Biochem J. 2005 Nov 1;391(Pt 3):623-9. PubMed PMID: 15987244; PubMed Central PMCID: PMC1276963.
  • van der Heide LP, Smidt MP. Regulation of FoxO activity by CBP/p300-mediated  acetylation. Trends Biochem Sci. 2005 Feb;30(2):81-6. PubMed PMID: 15691653.
  • Mathon DS, Lesscher HM, Gerrits MA, Kamal A, Pintar JE, Schuller AG, Spruijt  BM, Burbach JP, Smidt MP, van Ree JM, Ramakers GM. Increased gabaergic input to ventral tegmental area dopaminergic neurons associated with decreased cocaine reinforcement in mu-opioid receptor knockout mice. Neuroscience. 2005;130(2):359-67. PubMed PMID: 15664692.
  • Thuret S, AlavianKN, Gassmann M, Lloyd CK, Smits SM, Smidt MP, Klein R, Dyck RH, Simon HH. The neuregulin receptor, ErbB4, is not required for normal development and adult maintenance of the substantia nigra pars compacta. J Neurochem. 2004 Dec;91(6):1302-11. PubMed PMID: 15584907.
  • Smidt MP, Smits SM, Burbach JP. Homeobox gene Pitx3 and its role in the development of dopamine neurons of the substantia nigra. Cell Tissue Res. 2004Oct;318(1):35-43. Epub 2004 Aug 6. Review. PubMed PMID: 15300495.
  • Smits SM, Terwisscha van Scheltinga AF, van der Linden AJ, Burbach JP, Smidt  MP. Species differences in brain pre-pro-neurotensin/neuromedin N mRNA distribution: the expression pattern in mice resembles more closely that of primates than rats. Brain Res Mol Brain Res. 2004 Jun 18;125(1-2):22-8. PubMed PMID: 15193419.
  • Van Der Heide LP, Hoekman MF, Smidt MP. The ins and outs of FoxO shuttling: mechanisms of FoxO translocation and transcriptional regulation. Biochem J. 2004  Jun 1;380(Pt 2):297-309. Review. PubMed PMID: 15005655; PubMed Central PMCID: PMC1224192.
  • Smidt MP, Smits SM, Bouwmeester H, Hamers FP, van der Linden AJ, Hellemons AJ, Graw J, Burbach JP. Early developmental failure of substantia nigra dopamine  neurons in mice lacking the homeodomain gene Pitx3. Development. 2004 Mar;131(5):1145-55. PubMed PMID: 14973278.
  • Mathon DS, Kamal A, Smidt MP, Ramakers GM. Modulation of cellular activity and synaptic transmission in the ventral tegmental area. Eur J Pharmacol. 2003 Nov 7;480(1-3):97-115. Review. PubMed PMID: 14623354.
  • Smidt MP, Smits SM, Burbach JP. Molecular mechanisms underlying midbrain dopamine neuron development and function. Eur J Pharmacol. 2003 Nov 7;480(1-3):75-88. Review. PubMed PMID: 14623352.
  • 44: Smits SM, Ponnio T, Conneely OM, Burbach JP, Smidt MP. Involvement of Nurr1 in specifyingthe neurotransmitter identity of ventral midbrain dopaminergic neurons. Eur J Neurosci. 2003 Oct;18(7):1731-8. PubMed PMID: 14622207.
  • Kromkamp M, Uylings HB, Smidt MP, Hellemons AJ, Burbach JP, Kahn RS. Decreased thalamic expression of the homeobox gene DLX1 in psychosis. Arch Gen Psychiatry. 2003 Sep;60(9):869-74. PubMed PMID: 12963668.
  • JacobsFM,van der Heide LP, Wijchers PJ, BurbachJP,Hoekman MF, Smidt MP. FoxO6, a novel member of the FoxO class of transcription factors with distinct shuttling dynamics. J Biol Chem. 2003 Sep 19;278(38):35959-67. Epub 2003 Jul 11.  PubMed PMID: 12857750.
  • Burbach JP, Smits S, Smidt MP. Transcription factors in the development of midbrain dopamine neurons. Ann N Y Acad Sci. 2003 Jun;991:61-8. Review. PubMed PMID: 12846974.
  • Asbreuk CH, Vogelaar CF, Hellemons A, Smidt MP, Burbach JP. CNS expression pattern of Lmx1b and coexpression with ptx genes suggest functional cooperativity in the development of forebrain motor control systems. Mol Cell Neurosci. 2002 Nov;21(3):410-20. PubMed PMID: 12498783.
  • Asbreuk CH, van Schaick HS, Cox JJ, Smidt MP, Burbach JP. Survey for paired-like homeodomain gene expression in the hypothalamus: restricted expression patterns of Rx, Alx4 and goosecoid. Neuroscience. 2002;114(4):883-9. PubMed PMID: 12379244.
  • Asbreuk CH, van Schaick HS, Cox JJ, Kromkamp M, Smidt MP, Burbach JP. The homeobox genes Lhx7 and Gbx1 are expressed in the basal forebrain cholinergic system. Neuroscience. 2002;109(2):287-98. PubMed PMID: 11801365.
  • Smidt MP, Cox JJ, van Schaick HS, Coolen M, Schepers J, van der Kleij AM, Burbach JP. Analysis of three Ptx2 splice variants on transcriptional activity and differential expression pattern in the brain. J Neurochem. 2000 Nov;75(5):1818-25. PubMed PMID: 11032870.
  • Cazorla P, Smidt MP,O'Malley KL, Burbach JP. A response element for the homeodomain transcription factor Ptx3 in the tyrosine hydroxylase gene promoter.  J Neurochem. 2000 May;74(5):1829-37. PubMed PMID: 10800925.
  • Smidt MP, Asbreuk CH, Cox JJ, Chen H, Johnson RL, Burbach JP. A second independent pathway for development of mesencephalic dopaminergic neurons requires Lmx1b.Nat Neurosci. 2000 Apr;3(4):337-41.PubMedPMID:10725922.
  • Burbach JP, van Schaick H, Lopes da Silva S, Asbreuk CH, Smidt MP. Hypothalamic transcription factors and the regulation of the hypothalamo-neurohypophysial system. Adv Exp Med Biol. 1998;449:29-37. Review. PubMed PMID: 10026783.
  • Smidt MP, Snippe L, van Keulen G, Ab G. The bZip transcription factor vitellogenin-binding protein is post transcriptional down regulated in chicken liver. Eur J Biochem. 1998 Aug 15;256(1):106-11. PubMed PMID: 9746352.
  • Saucedo-Cardenas O, Quintana-Hau JD, Le WD, Smidt MP, Cox JJ, De Mayo F, Burbach JP, Conneely OM. Nurr1 is essential for the induction of the dopaminergic phenotype and the survival of ventral mesencephalic late dopaminergic precursor neurons. Proc Natl Acad Sci U S A. 1998 Mar 31;95(7):4013-8. PubMed PMID: 9520484; PubMed Central PMCID: PMC19954.
  • Smidt MP, van Schaick HS, Lanctôt C, Tremblay JJ, Cox JJ, van der Kleij AA, Wolterink G, Drouin J, Burbach JP. A homeodomain gene Ptx3 has highly restricted  brain expression in mesencephalic dopaminergic neurons. Proc Natl Acad Sci U S A. 1997 Nov 25;94(24):13305-10. PubMed PMID: 9371841; PubMed Central PMCID: PMC24304.
  • van Schaick HS, Smidt MP, Rovescalli AC, Luijten M, van der Kleij AA, Asoh S, Kozak CA, Nirenberg M, Burbach JP. Homeobox gene Prx3 expression in rodent brain  and extraneural tissues. Proc Natl Acad Sci U S A. 1997 Nov 25;94(24):12993-8. PubMed PMID: 9371788; PubMed Central PMCID: PMC24251.
  • Smidt MP, Russchen B, Snippe L, Wijnholds J, Ab G. Cloning and characterisation of a nuclear, site specific ssDNA binding protein. Nucleic Acids Res. 1995 Jul 11;23(13):2389-95. PubMed PMID: 7630716; PubMed Central PMCID: PMC307042.
  • Smidt MP, Wijnholds J, Snippe L, van Keulen G, Ab G. Binding of a bZip protein to the estrogen-inducibleapoVLDL II promoter. Biochim Biophys Acta. 1994 Sep 13;1219(1):115-20. PubMed PMID: 8086448.
  • van der Ploeg J, Smidt MP, Landa AS, Janssen DB. Identification of chloroacetaldehyde dehydrogenase involved in 1,2-dichloroethane degradation. Appl Environ Microbiol. 1994 May;60(5):1599-605. PubMed PMID: 16349259; PubMed Central PMCID: PMC201523.
  • Beintema JJ, Stam WT, Hazes B, Smidt MP. Evolution of arthropod hemocyanins and insect storage proteins (hexamerins). Mol Biol Evol. 1994 May;11(3):493-503.  PubMed PMID: 8015442.
  • Van Rijssel M, Smidt MP, Van Kouwen G, Hansen TA. Involvement of an Intracellular Oligogalacturonate Hydrolase in Metabolism of Pectin by Clostridium thermosaccharolyticum. Appl Environ Microbiol. 1993 Mar;59(3):837-42. PubMed PMID: 16348892; PubMed Central PMCID: PMC202197.

 

Molecular Neuroscience Team

Marten Smidt

Prof. dr. Marten Smidt

Principle investigator

Marco Hoekman

Dr. Marco Hoekman

Assistant professor

Role of Clock and Forkhead proteins in cortical development.

Lars van der Heide

Dr. Lars van der Heide

Assistant professor

Survival mechanisms in neuronal development 

Hans van Hooft

Dr. Johannes A. (Hans) van Hooft

Assistant professor

Neurophsysiology

Serotonin 5-HT3 receptor-mediated signaling in cortical development and function.

Frank Jacobs

Dr. Frank M.J. Jacobs

Assistant professor

Primate genome evolution and the impact on human brain development

 

Ricardo Paap

Ricardo Paap

PhD Student

Molecular mechanisms of cortical development and function 

Simone Mesman

Simone Mesman

PhD student

Molecular coding of dopaminergic subsets related to the ventricular zone coding 

Willemieke Kouwenhoven

Willemieke Kouwenhoven

PhD student

Molecular mechanisms of En1 action 

Lars von Oerthel

Lars von Oerthel

Research technician, FACS operator,  Lab-head

Erik van Heesbeen

Erik van Heesbeen

PhD student.

Epigenetics of neuronal development 

Iris Wever

Iris Wever

PhD student

The epigentic influence of Lmx1a and Lmx1b 

Gerrald Lodewijk

Gerrald Lodewijk

PhD student (in the lab of Frank Jacobs)

Primate genome evolution and the impact on human brain development

Nina Haring

PhD student

Molecular programming of mdDA neuronal subsets.

Group Picture 2013

Group Picture 2013 at the University of Amsterdam, FNWI building, SILS common room

Molecular NeuroSciences (MNS)

The function of the brain is the result of an extreme complex integration of signaling units: the neuron. In order to understand the function in health and disease it is essential to understand the fundamental mechanisms underlying neuronal function. With the progression made in genetics it has become the great ambition to understander what all these genes are doing in neuronal systems. The basic understanding of molecular principles hold the key towards novel treatment paradigms for essential psychiatric and neurological diseases as schizophrenia and Parkinson.

The Molecular NeuroSciences master track is providing a training platform for master student that have the ambition to play a major role in solving the diseases of today and tomorrow.

Goals

The goals of the Molecular NeuroScience track are as follows:

  • Provide the essential theoretical framework in molecular neurosciences

  • Prepare the student to be a critical researcher

  • Prepare the student to work independently in a molecular neuroscience lab.

  • Prepare the student to report on his/her results in written and spoken form.

  • Train the student in the line: research question → design experiment → interpret result → define following research question.

  • Train the student in applying for research funding.

Programme outline

The MNS track is initiated with an obligatory start course of 3 months (18EC). The course contains 3 different topics:

  • Development and specification of neuronal systems

  • Signaling pathways in neuronal systems

  • Stem-cell fate and cortical genesis.

In order to integrate the material and to guide the student, all topics are founded with practical work:1 week full time per topic. These practicals will include state of the art techniques as in-utero and ex-vivo gene transfer in the brain and FACS. Moreover, a theoretical assignment is placed over the complete course which integrates all the topics and practical training.

In this part of the master the trainee will be prepared to work independently in a molecular neuroscience lab.

After the course a first internship is planned of about 40 EC and the first master year will be finalized by gathering all the trainees to a student symposium (~ 2EC) were the data of the internships will be presented and discussed with colleges and supervisors.

In the second year a second internship will be planned (~48 EC) with the goal to go abroad. In conjuncture with this internship a second optional course can be followed in order to obtain a formal certificate in animal work. The second year will be finalized by writing a research thesis (review of literature; 12 EC).

It is possible to combine this master with an different major. In general the fist year will be followed as scheduled and the second year can be filled with a different schedule n the required direction. Also, different additional course (at the UVA or other universities) can be followed in the second year.

 

Special elective course Art. 9 WOD.

Being an integral part of this program, we offer UvA master students to obtain their Art. 9 license. Therefore we organize an elective course Art. 9 WOD within the Molecular Neuroscience program. 

Education

Involved courses at the UvA: 

  • Ontwikkelingsbiologie, Ontwikkelingspsychologie & Taal, (Bachelor PB, Year 2)
  • Molecular biology of the cell ( Bachelor PB, year 1)
  • Techniques in Molecular biology (Bachelor PB, year2/3)
  • Introduction in the Neurobiology, (Bachelor medical sciences, year 3)
  • New Art. 9, WOD course scheduled for june 2014; Provides the formal certification (Art. 9) for animal experimentation in the EU.
  • Master program Molecular NeuroScience (MNS)/NeuroDevelopment (2 years)

Internship possibilities

Please contact marten smidt, or other lab members by email for new internship possibilities; see the labmembers tab.

 

Managment

Chairman of the exam committee of the Bachelor Psychobiology (2012-current).

Chairman/director of the Neurobiology cluster of the master Biomedical sciences (2012-current).

Chairman of the VIDI-ALW committee (2011-2014).

 

EU-Programs

Marten Smidt has been a coordinator of the MdDAneurodev program (FP7 collaborative project; 222999) "Molecular coding and subset specification of dopamine neurons generating the meso-limbic andf nigrostriatal system"

 

The project was evaluated as excellent en resulted in many publications on the topic by the respective consortium members. The project was finalized at the end of 2012.

Consortium partners:

Prof. W. Wurst; Prof. W. Driever; Prof. J Pasterkamp; Prof. O. Marin; Prof T. Perlmann; Prof. A. Prochiantz and Prof A. Simeone.

 

**Please see the downloads area for the eu published report. 

 

 

2014

2013

2012

2011

2012

2011

  • J.P.H. Burbach, H.S.A. van Schaick, S.N. Lopes da Silva, C.H.J. Asbreuk & M.P. Smidt (2011). Hypothalamic transcription factors and the regulation of the hypothalamo-neurohypophysial system. In H.H. Zingg, C.W. Bourque & D.G. Bichet (Eds.), Vasopressin and Oxytocin. Molecular, Cellular and Clinical Advances (pp. 29-37). New York: Plenum Press.

2009

  • M.P. Smidt (2009). Specific vulnerability of substantia nigra compacta neurons. In G. Giovanni, V. Di Matteo & E. Esposito (Eds.), Birth, life and death of dopaminergic neurons in the substantia nigra (Journal of neural transmission. Supplement, 73) (pp. 39-47). New York: Springer- Verlag.
  • M.P. Smidt & J.P.H. Burbach (2009). Terminal differentiation of mesodiencephalic dopaminergic neurons: the role of Nurr1 and Pitx3. In R.J. Pasterkamp, M.P. Smidt & J.P.H. Burbach (Eds.), Development and engineering of dopamine neurons (Advances in experimental medicine and biology, 651) (pp. chp 4). New York: Springer Science + Business Media LLC.
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