RCMI Coordinating Center (RCMI CC) Header Logo

Andreas Kottmann

TitlePrincipal Investigator
Faculty RankAssociate Professor
InstitutionCity College, CUNY
DepartmentPhysiology, Pharmacology, Neuroscience
AddressMarshak Science Building
Room 907
160 Convent Avenue
New York NY 10031
Phone212 650 6815
vCardDownload vCard
    Other Positions
    TitleAssistant Professor of Neuroscience
    InstitutionColumbia University
    DepartmentPathology and Cell Biology

    Collapse Overview 
    Collapse overview
    The Kottmann Laboratory studies the regulation of structural plasticity underlying motor adaption and procedural -learning and -memory. While we conduct basic, molecular biology based research using genetically altered mice, our work is of high clinical relevance for neurological and neuropsychiatric disorders involving the basal ganglia such as Parkinson's disease and addictive states in which behavioral patterns are disturbed, and for spinal cord injury and diseases involving spinal motor neurons and skeletal muscle. Our approaches and our genetic and viral research tools might have utility beyond our immediate research interests and we invite collaborations. The Kottmann laboratory has three main areas of focus:
    (1) Regulation of structural plasticity in basal ganglia circuits:
    Many parts of the CNS in higher vertebrates are constantly remodeled during adult life allowing memory formation and learning. It is widely assumed that plasticity processes underlying memory and learning must be closely regulated by homeostatic feedback in order to preserve overall stability and function of the mature CNS. Computations in the basal ganglia are critical for procedural -learning and -memory and the acquisition of skilled motor behaviors and motor habits. The basal ganglia also represent the anatomic substrate for numerous neurodegenerative and psychiatric disorders including Parkinson’s disease (PD), Huntington disease (HD), addiction and schizophrenia. It is hypothesized that corrupted regulation of structural plasticity could contribute to the manifestation of structural and functional pathology of diseases impacting the adult basal ganglia. The mechanisms maintaining cellular and neurochemical homeostasis in the mature basal ganglia in the healthy brain are not fully elucidated but signaling by neurotrophic factors has emerged as a likely process.
    Using a candidate gene approach we discovered that all mesencephalic dopamine (DA) neurons express the cell signaling molecule Sonic Hedgehog (Shh) throughout life. To test the physiological relevance of Shh expression by DA neurons we produced a mouse line in which Shh expression is genetically ablated in mature DA neurons. These studies demonstrated that non cell autonomous Shh signaling originating from DA neurons is absolutely required for the long term maintenance of striatal cholinergic (ACh) and fast spiking (FS) interneurons as well as DA neurons.
    Further experimentation revealed that DA neurons of the mesencephalon and their projection targets ACh and FS neurons are linked together in a reciprocal trophic support loop: DA neurons produce Shh which acts on ACh and FS neurons, while ACh and FS neurons produce the dopaminotrophic factor GDNF (glia derived neurotrophic factor). Using mice with conditional ablation of GDNF or of the receptor for GDNF, Ret, in conjunction with acute manipulations of Shh signaling, we demonstrated that Shh signaling inhibits the transcription of GDNF in ACh and FS neurons and, conversely, that GDNF signaling inhibits the transcription of Shh in DA neurons. Our data reveals the existence of a reciprocal trophic support loop with rheostat properties: the attenuation of Shh expression in DA neurons by physiological cell stress, results in the relief of repression of GDNF in synaptically connected ACh and FS neurons and, in return, in enhanced expression of GDNF leading to greater trophic support of physiologically compromised DA neurons. Similarly, the attenuation of GDNF expression in ACh or FS neurons will result in increased Shh expression in DA neurons providing elevated trophic support to stressed ACh or FS neurons in return.
    Supporting the notion that compromised neurotrophic factor signaling could cause basal ganglia diseases, we observe in animals that cannot express Shh in DA neurons adult onset and progressive locomotion and gait disturbances reminiscent of PD that can be alleviated by treatment with L-Dopa, the standard pharmacological strategy for the management of PD.
    Interestingly, both GDNF and Shh also have neuromodulatory activity. We therefore tested the impact of Shh signaling on ACh neuron activity. These experiments revealed that Shh regulates the setpoint of the level of extra cellular acetylcholine (tone) by regulating muscarinic autoreceptor M2 transcription.
    Guided by these experiments we currently investigate whether Shh expression by DA neurons influences the rate of reinforcement learning, the balance between goal oriented and habitual motor behaviors, and the kinetics by which motor habits are formed.
    Using conditional gene ablation approaches, we also have begun an investigation whether there are other sources in the adult brain besides DA neurons that could provide Shh to the basal ganglia.
    Publication: Gonzalez Reyes et al.,(2012) “Sonic Hedgehog Maintains Cellular and Neurochemical Homeostasis in the Adutl Nigrostriatal Circuit.” Neuron 75, 306-319.
    (2) Regulation of neurogenesis in the adult forebrain:
    In translational stem cell research, particular interest has been devoted to neural precursor/stem cells resident in regions that display neurogenesis in adult mammals. This is due to the promise that neuronal stem cells resident in the adult brain could be coaxed into replenishing brain tissue with functional neurons and glia that are lost in neurodegenerative disease or aging. In principal support of this notion it has been found that many neurodegenerative diseases lead to changes in the cytoarchitecture and qualitative outcome of neurogenesis in the subventricular zone (SVZ) of the forebrain, pointing to pathological as well as adaptive and possibly corrective functional alterations in the SVZ dependent on the specific disease. A physiological adaptation of neurogenic outcome to current physiological needs of the adult CNS requires at least two functions:
    a) The generation of a cell type specific signal for functional and/or structural deterioration
    b) A mechanism by which this signal is translated into appropriate alterations in cell fate determination in the neurogenic niche.
    We demonstrate that the morphogen Sonic Hedgehog (Shh), expressed outside of the germinal niche by adult dopaminergic (DA) neurons of the mesencephalon, is a key regulator of adult neurogenesis. We show that the genetic ablation of Shh from DA neurons causes an overall reduction of neurogenic activity, but an increase in the numbers of dopaminergic, periglomerular neurons of the olfactory bulb, and olfactory dysfunction. In particular, we produced evidence that Shh expression by DA neurons is up-regulated dynamically in correlation with the severity of cell physiological stress and neuronal dysfunction in connected neurons (Gonzalez et al., 2012). Thus our data suggests that Shh expressed by DA neurons could be both, a cell type specific sentinel for neuronal dysfunction and a morphogen whose expression at different levels could skew the qualitative outcome of SVZ neurogenesis towards cell identities of physiological need.
    Current work aims to establish an allelic series of Shh expression levels by DA neurons and producing conditional overexpression alleles for Shh in DA neurons that can be switched on and off in mice. We also establish biochemical and functional assays to quantify the amount of biological active Shh produced by DA neurons and delivered to the SVZ. Determination of the qualitative outcome of SVZ neurogenesis as a function of different amounts of Shh delivered by DA neurons will allow us to determine the Shh dose dependent production of particular neuronal cell fates. We will then use conditional cell fate tracing to determine the destination and potential function of neurons born in response to Shh signaling from DA neurons.
    Publication: manuscript in preparation.
    (3) Function of trophic factor and morphogen production and signaling by spinal motor neurons:
    Within the spinal motor neuron (MN) unit several tissues are interconnected that display drastically different capacities for plasticity and repair: MNs are thought not to be replenished and to retain their muscle subtype specific phenotype throughout life once born. In contrast, within the spinal cord and along their peripheral axonal projections, MNs are supported by glia, which demonstrate remarkable phenotypic transitions, expansion and turnover during disease and upon physical injury. The sole targets of MNs, skeletal muscle fibers, react to changes in bio mechanical demands and injury by the de novo production of task appropriate contractile elements and entire fibers. The plasticity and regenerative capacity of glia and muscle tissues results from germinal niches, that are formed by (1) neural stem cells resident in the ependymal cell layer surrounding the central canal in the mature spinal cord, (2) satellite (muscle stem-) cells present in each muscle fiber, and (3) the production of mitotically active repair cells, “Bungner cells”, by de-differentiation of mature Schwann cells along MN axons. The plasticity and repair processes are selective for the muscle and nerve involved. How these processes are induced, and whether and how they are coordinated is not well understood.
    We and others found that mature MNs can express the morphogen Sonic Hedgehog (Shh) throughout life. Shh is essential for the ordered differentiation and congruent growth of many tissues and organs during embryogenesis where it becomes secreted from Spemann type organizer tissues like notochord and floorplate, forming gradients of morphogenic activity that results in the tissue patterning of abutting fields of naïve precursor cells. We observe that in mature MNs Shh expression is induced by muscle denervation. We also reveal that Shh production by MNs is essential for the maintenance of slow twitch muscle fibers suggesting that MN produced Shh is transported through and released from MN axons. Based on our data we hypothesize that motor units involved in functional or structural repair or plasticity, orchestrate motor unit wide processes through the graded up-regulation of Shh in effected MNs. Using a combination of genetic gain and loss of function paradigms, previously established by my lab (Gonzalez-Reyes 2012) in combination with disease- and injury- models in mice, we investigate whether MNs in the adult spinal cord act as spatially restricted signaling centers by secreting graded levels of Shh to regulate the activity and differentiation stem cells within the mature spinal cord and, transported by motor neuron axons, orchestrate muscle plasticity and repair, and coordinate Schwann cell responses to injury.
    Publication: manuscript in preparation.

    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.
    Newest   |   Oldest   |   Most Cited   |   Most Discussed   |   Timeline   |   Field Summary   |   Plain Text
    PMC Citations indicate the number of times the publication was cited by articles in PubMed Central, and the Altmetric score represents citations in news articles and social media. (Note that publications are often cited in additional ways that are not shown here.) Fields are based on how the National Library of Medicine (NLM) classifies the publication's journal and might not represent the specific topic of the publication. Translation tags are based on the publication type and the MeSH terms NLM assigns to the publication. Some publications (especially newer ones and publications not in PubMed) might not yet be assigned Field or Translation tags.) Click a Field or Translation tag to filter the publications.
    1. Malave L, Zuelke DR, Uribe-Cano S, Starikov L, Rebholz H, Friedman E, Qin C, Li Q, Bezard E, Kottmann AH. Dopaminergic co-transmission with sonic hedgehog inhibits abnormal involuntary movements in models of Parkinson's disease and L-Dopa induced dyskinesia. Commun Biol. 2021 09 22; 4(1):1071. PMID: 34552196.
    2. Starikov L, Kottmann AH. Diminished Ventral Oligodendrocyte Precursor Generation Results in the Subsequent Over-production of Dorsal Oligodendrocyte Precursors of Aberrant Morphology and Function. Neuroscience. 2020 12 01; 450:15-28. PMID: 32450295.
      Citations: 5     Fields:    Translation:AnimalsCells
    3. Castello J, Cortés M, Malave L, Kottmann A, Sibley DR, Friedman E, Rebholz H. Publisher Correction: The Dopamine D5 receptor contributes to activation of cholinergic interneurons during L-DOPA induced dyskinesia. Sci Rep. 2020 Mar 13; 10(1):4974. PMID: 32165689.
      Citations:    Fields:    
    4. Castello J, Cortés M, Malave L, Kottmann A, Sibley DR, Friedman E, Rebholz H. The Dopamine D5 receptor contributes to activation of cholinergic interneurons during L-DOPA induced dyskinesia. Sci Rep. 2020 02 13; 10(1):2542. PMID: 32054879.
      Citations: 4     Fields:    Translation:HumansAnimalsCells
    5. Gonzalez-Reyes LE, Chiang CC, Zhang M, Johnson J, Arrillaga-Tamez M, Couturier NH, Reddy N, Starikov L, Capadona JR, Kottmann AH, Durand DM. Sonic Hedgehog is expressed by hilar mossy cells and regulates cellular survival and neurogenesis in the adult hippocampus. Sci Rep. 2019 11 22; 9(1):17402. PMID: 31758070.
      Citations: 6     Fields:    Translation:Cells
    6. Gonzalez-Reyes LE, Verbitsky M, Blesa J, Jackson-Lewis V, Paredes D, Tillack K, Phani S, Kramer ER, Przedborski S, Kottmann AH. Sonic hedgehog maintains cellular and neurochemical homeostasis in the adult nigrostriatal circuit. Neuron. 2012 Jul 26; 75(2):306-19. PMID: 22841315.
      Citations: 60     Fields:    Translation:AnimalsCells
    7. Desouza LA, Sathanoori M, Kapoor R, Rajadhyaksha N, Gonzalez LE, Kottmann AH, Tole S, Vaidya VA. Thyroid hormone regulates the expression of the sonic hedgehog signaling pathway in the embryonic and adult Mammalian brain. Endocrinology. 2011 May; 152(5):1989-2000. PMID: 21363934.
      Citations: 18     Fields:    Translation:AnimalsCells
    8. Kolterud A, Grosse AS, Zacharias WJ, Walton KD, Kretovich KE, Madison BB, Waghray M, Ferris JE, Hu C, Merchant JL, Dlugosz AA, Kottmann AH, Gumucio DL. Paracrine Hedgehog signaling in stomach and intestine: new roles for hedgehog in gastrointestinal patterning. Gastroenterology. 2009 Aug; 137(2):618-28. PMID: 19445942.
      Citations: 76     Fields:    Translation:AnimalsCells
    9. Schwegmann A, Guler R, Cutler AJ, Arendse B, Horsnell WG, Flemming A, Kottmann AH, Ryan G, Hide W, Leitges M, Seoighe C, Brombacher F. Protein kinase C delta is essential for optimal macrophage-mediated phagosomal containment of Listeria monocytogenes. Proc Natl Acad Sci U S A. 2007 Oct 09; 104(41):16251-6. PMID: 17913887.
      Citations: 14     Fields:    Translation:AnimalsCells
    10. Yun SW, Platholi J, Flaherty MS, Fu W, Kottmann AH, Toth M. Fmrp is required for the establishment of the startle response during the critical period of auditory development. Brain Res. 2006 Sep 19; 1110(1):159-65. PMID: 16887106.
      Citations: 20     Fields:    Translation:Animals
    11. Leonardo ED, Richardson-Jones JW, Sibille E, Kottman A, Hen R. Molecular heterogeneity along the dorsal-ventral axis of the murine hippocampal CA1 field: a microarray analysis of gene expression. Neuroscience. 2006; 137(1):177-86. PMID: 16309847.
      Citations: 25     Fields:    Translation:Animals
    12. Lewis PM, Gritli-Linde A, Smeyne R, Kottmann A, McMahon AP. Sonic hedgehog signaling is required for expansion of granule neuron precursors and patterning of the mouse cerebellum. Dev Biol. 2004 Jun 15; 270(2):393-410. PMID: 15183722.
      Citations: 143     Fields:    Translation:AnimalsCells
    13. Jeong J, Mao J, Tenzen T, Kottmann AH, McMahon AP. Hedgehog signaling in the neural crest cells regulates the patterning and growth of facial primordia. Genes Dev. 2004 Apr 15; 18(8):937-51. PMID: 15107405.
      Citations: 271     Fields:    Translation:HumansAnimalsCells
    14. Brown LY, Kottmann AH, Brown S. Immunolocalization of Zic2 expression in the developing mouse forebrain. Gene Expr Patterns. 2003 Jun; 3(3):361-7. PMID: 12799086.
      Citations: 19     Fields:    Translation:AnimalsCells
    15. Kalachikov S, Evgrafov O, Ross B, Winawer M, Barker-Cummings C, Martinelli Boneschi F, Choi C, Morozov P, Das K, Teplitskaya E, Yu A, Cayanis E, Penchaszadeh G, Kottmann AH, Pedley TA, Hauser WA, Ottman R, Gilliam TC. Mutations in LGI1 cause autosomal-dominant partial epilepsy with auditory features. Nat Genet. 2002 Mar; 30(3):335-41. PMID: 11810107.
      Citations: 159     Fields:    Translation:HumansAnimalsCells
    16. Zou YR, Kottmann AH, Kuroda M, Taniuchi I, Littman DR. Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development. Nature. 1998 Jun 11; 393(6685):595-9. PMID: 9634238.
      Citations: 706     Fields:    Translation:AnimalsCells
    17. Kottmann AH, Zevnik B, Welte M, Nielsen PJ, Köhler G. A second promoter and enhancer element within the immunoglobulin heavy chain locus. Eur J Immunol. 1994 Apr; 24(4):817-21. PMID: 8149952.
      Citations: 5     Fields:    Translation:AnimalsCells
    18. Dirkes G, Köhler G, Kottmann AH. Sequence and structure of the mouse IgH DQ52 5' region. Immunogenetics. 1994; 40(5):379. PMID: 7927543.
      Citations:    Fields:    Translation:AnimalsCells
    19. Kottmann AH, Brack C, Eibel H, Köhler G. A survey of protein-DNA interaction sites within the murine immunoglobulin heavy chain locus reveals a particularly complex pattern around the DQ52 element. Eur J Immunol. 1992 Aug; 22(8):2113-20. PMID: 1639106.
      Citations: 3     Fields:    Translation:AnimalsCells
    20. Güssow D, Rein R, Ginjaar I, Hochstenbach F, Seemann G, Kottman A, Ploegh HL. The human beta 2-microglobulin gene. Primary structure and definition of the transcriptional unit. J Immunol. 1987 Nov 01; 139(9):3132-8. PMID: 3312414.
      Citations: 84     Fields:    Translation:HumansCells
    21. Kottmann AH, Seemann GH, Guessow HD, Roos MH. DNA sequence of the coding region of the HLA-B44 gene. Immunogenetics. 1986; 23(6):396-400. PMID: 3459708.
      Citations: 19     Fields:    Translation:HumansCells
    Kottmann's Networks
    Click the
    buttons for more information and interactive visualizations!
    Concepts (144)
    Similar People (60)
    RCMI CC is supported by the National Institute on Minority Health and Health Disparities, National Institutes of Health (NIH), through Grant Number U24MD015970. The contents of this site are solely the responsibility of the authors and do not necessarily represent the official views of the NIH

    For technical support please contact support