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Evan S. Deneris, Ph.D.

Evan S. Deneris, Ph.D.
Interim Chair of Department of Neurosciences
Department of Neurosciences
Case Western Reserve University

School of Medicine
10900 Euclid Ave
Cleveland OH, 44106-4975

Phone : (216) 368-8725
Fax : (216) 368-4650
Email :


Research in the Deneris lab is aimed at understanding the genetic mechanisms that act across the lifespan to regulate serotonin system function and to determine how these mechanisms impact serotonin modulated behaviors. Our studies have identified transcription factors that function in an embryonic regulatory network to specify serotonin neurons in the mouse ventral hindbrain.

Current research in the lab is focussed on using a recently developed temporally controlled genetic targeting approach to investigate the requirement for ongoing serotonergic transcription in serotonin system maturation and maintenance across the lifespan. Our new findings have shown that, Pet-1, a key factor in the serotonergic specification network continues to function at subsequent stages of serotonin system maturation to regulate serotonergic axonal innervation patterns and acquisition of intrinsic autoregulatory pathways that modulate serotonin neuron firing and transmitter release. Pet-1-dependent transcription is still needed in adult serotonin neurons to directly regulate brain serotonin synthesis and reuptake and to maintain emotional behaviors. These findings demonstrate that alterations in serotonergic transcriptional networks at any stage of life can disrupt serotonin system modulation of behavior and physiology.

Htr1A and Htr1B Autoregulatory Pathways

Ongoing Pet-1 expression is required after serotonergic neurogenesis for induction of the autoregulatory receptors that control 5HT neuron firing and transmitter release.

Whole cell recordings in YFP-marked, conditionally targeted Pet-1 mutant 5HT neurons shows an absence of 5HT 1A agonist responses.

Induction of 5HT 1A and 5HT 1B receptor gene expression, which normally occurs around E15, fails in conditionally targeted Pet-1 mutant mice.

We have developed new genetic-based approaches to investigate the physiological importance of serotonin system function. These approaches rely on BAC transgenic tools that were made possible by the identification of the Pet-1 cis regulatory region that directs highly reproducible expression of transgenes in developing and adult brain 5HT neurons. These tools have enabled the genetic marking of brain 5HT neurons for whole cell patch clamp recordings and purification of these neurons by FACS. They have also allowed us to target gene expression specifically in 5HT neurons at any stage of life. Our new approaches have resulted in a series of published studies that demonstrated that disruption of the transcription regulatory network that governs serotonergic neurogenesis is a potential mechanism for behavioral pathogenesis as alterations in the network cause dramatic abnormalities in emotional behaviors, maternal behavior, inflammatory pain, respiratory system maturation and thermoregulation.

Future studies are aimed at determining the importance Pet-1-dependent transcription in the early postnatal critical period for adult antipsychotic drug responses, maternal behavior and chronic stress and to use deep sequencing approaches to determine the mechanisms of Pet-1 function in serotonin neurons.


  1. Issler O, Haramati S, Paul ED, Maeno H, Navon I, Zwang R, Gil S, Mayberg HS, Dunlop BW, Menke A, Awatramani R, Binder EB, Deneris ES, Lowry CA, Chen A. (2014)
    MicroRNA 135 Is Essential for Chronic Stress Resiliency, Antidepressant Efficacy, and Intact Serotonergic Activity. Neuron. 83:344-360.
  2. Deneris, E. and Hobert, O. (2014)
    Maintenance of postmitotic neuronal cell identity Nature Neuroscience. 17:899-907.
  3. Fox, S.R. and Deneris, E.S. (2012)
    Engrailed is required in maturing serotonin neurons to regulate the cytoarchitecture and survival of the dorsal raphe nucleus. Journal of Neuroscience. 32:7832-7842.
  4. Liu, C. and Deneris, E.S. (2011)
    Transcriptional control of serotonin-modulated behavior and physiology. Neuropsychopharmacology. 36:361-362.
  5. Yadav, P.N., Abbas, A.I., Farrell, M.S., Setola, V., Sciaky, N., Huang, X.P., Kroeze, W.K., Michael J. Keiser, M.J., Irwin, J.J., Shoichet, B.K., Deneris, E.S., Gingrich, J., Beck, S.G., Roth, B.L. (2011)
    The Pre-synpatic Component of the Serotonergic System is Required for Clozapine’s Efficacy. Neuropsychopharmacology. in press
  6. Liu, C., Maejima, T., Wyler, S., Casadesus, G., Herlitze, Deneris, E.S. (2010)
    Pet-1 is Required Across Different Stages of Life to Regulate Serotonergic Function. Nat. Neuroscience. 13:1190-1198 PMCID: PMC2947586.
  7. Oh, E., Maejima, T, Liu, C., Deneris, E., Herlitze, S. (2010)
    Substitution of 5-HT1A receptor signaling by a light-activated G protein-coupled receptor J. Biol. Chem. 285:30825-30836.
  8. Cummings KJ, Li A, Deneris E, Nattie E. (2010)
    Bradycardia in serotonin deficient Pet-1-/- mice: influence of respiratory dysfunction and hyperthermia over the first two postnatal weeks. Am J Physiol Regul Integr Comp Physiol. 298:R1333-1342.
  9. Wylie, C.J., Hendricks, T.J., Zhang, B., Wang, L., Lu, P., Leahy, P., Fox, S., Maeno, H., and Deneris, E.S. (2010)
    Distinct transcriptomes define rostral and caudal serotonin neurons J. Neurosci. 30:670-684.
  10. Hawthorne, A.L., Wylie, C.J., Landmesser, L.T., Deneris, E.S. and Silver, J. (2010)
    Serotonergic neurons labeled by ePet-EYFP migrate radially through the neuroepithelium by somal translocation J. Neurosci. 30:420-430 PMC2855244.
  11. Corcoran AE, Hodges MR, Wu Y, Wang W, Wylie CJ, Deneris ES, Richerson GB. (2009) (2009)
    Medullary serotonin neurons and central CO(2) chemoreception Respir Physiol Neurobiol. 168:49-58.
  12. Krueger, K.C. and Deneris, E.S. (2008)
    Serotonergic transcription of human FEV reveals direct GATA factor interactions and fate of Pet-1 deficient serotonin neuron precursors. J. Neurosci. 28:12748-12758 PMCID: PMC2610260.
  13. Lerch-Haner, J.K., Frierson, D., Crawford, L., Beck, S. and Deneris, E.S. (2008)
    Serotonergic transcriptional programming determines maternal behavior and offspring survival. Nat. Neurosci. 11:1001-1003 PMCID: PMC2679641.
  14. Jensen, P., Farago, A.F., Awatramani, R.B., Scott, M.M., Deneris, E.S. and Dymecki, S.M. (2008)
    Redefining the central serotonergic system based on genetic lineage. Nat. Neurosci. 11:417-419.
  15. Hodges, M.R., Tattersall, G.J., Harris, M.B., McEvoy, S.D., Richerson, D.N., Deneris, E.S., Johnson, R. L., Chen, Z. F., Richerson, G.B. (2008)
    Defects in breathing and thermoregulation in mice with near-complete absence of central serotonin neurons, has been received. J. Neurosci. 28:2495-2505.
  16. Erickson, J.T., Shafer, G., Rossetti, M.D., Wilson, C. G., and Deneris, E.S. (2007)
    Arrest of 5HT neuron differentiation delays respiratory maturation and impairs neonatal homeostatic responses to environmental challenges Respir. Physiol. Neurobiol. 159:85-101 PMCID: PMC2593840.
  17. *Zhao, Z. Q., *Scott, M.M., Chiechio, S., Wang, J.S., Renner, K.J., Gereau, R.W. IV Johnson, R.L., Deneris, E.S., and Chen, Z.F. (2006)
    Lmx1b is required for maintenance of central serotonergic neurons and mice lacking central serotonergic system exhibit normal locomotive activity. J. Neurosci. 26:12781-12788.
  18. Xu, X, Scott, M.M. and Deneris, E. (2006)
    Shared long-range regulatory elements coordinate expression of a gene cluster encoding nicotinic receptor heteromeric subtypes Mol. Cell. Biol. 26:5636-5649.
  19. Scott, M.S., Wylie, C.W., Lerch, J.K., Murphy, R., Lobur, K., Herlitze, S., Jiang, W., Conlon, R.A., Strowbridge, B., and Deneris, E.S. (2005)
    A genetic approach to access serotonin neurons for in vivo and in vitro studies. PNAS. 2005 Nov 8; 102(45):16472-16477 PMC1283423. 2005/10/26 [aheadofprint].
  20. Scott MM, Krueger KC, Deneris ES. (2005)
    A differentially autoregulated Pet-1 enhancer region is a critical target of the transcriptional cascade that governs serotonin neuron development. J Neurosci. 2005 Mar 9; 25(10):2628-2636.
  21. Scott MM, Deneris ES. (2005)
    Making and breaking serotonin neurons and autism. Int J Dev Neurosci. 2005 Apr-May; 23(2-3):277-285.
  22. Hendricks TJ, Fyodorov DV, Wegman LJ, Lelutiu NB, Pehek EA, Yamamoto B, Silver J, Weeber EJ, Sweatt JD, Deneris ES. (2003)
    Pet-1 ETS gene plays a critical role in 5-HT neuron development and is required for normal anxiety-like and aggressive behavior. Neuron. 2003 Jan 23; 37(2):233-247.
  23. Francis N, Deneris ES. (2002)
    Retinal neuron activity of ETS domain-binding sites in a nicotinic acetylcholine receptor gene cluster enhancer. J Biol Chem. 2002 Feb 22; 277(8):6511-6519. 2001/12/04 [aheadofprint].
  24. Zhou Y, Deneris E, Zigmond RE. (2001)
    Nicotinic acetylcholine receptor subunit proteins alpha7 and beta4 decrease in the superior cervical ganglion after axotomy. J Neurobiol. 2001 Feb 15; 46(3):178-192.
  25. McDonough J, Francis N, Miller T, Deneris ES. (2000)
    Regulation of transcription in the neuronal nicotinic receptor subunit gene cluster by a neuron-selective enhancer and ETS domain factors. J Biol Chem. 2000 Sep 15; 275(37):28962-28970.
  26. Deneris ES, Francis N, McDonough J, Fyodorov D, Miller T, Yang X. (2000)
    Transcriptional control of the neuronal nicotinic acetylcholine receptor gene cluster by the beta43' enhancer, Sp1, SCIP and ETS transcription factors. Eur J Pharmacol. 2000 Mar 30; 393(1-3):69-74.
  27. Hendricks T, Francis N, Fyodorov D, Deneris ES. (1999)
    The ETS domain factor Pet-1 is an early and precise marker of central serotonin neurons and interacts with a conserved element in serotonergic genes. J Neurosci. 1999 Dec 1; 19(23):10348-10356.
  28. Zhou Y, Deneris E, Zigmond RE. (1998)
    Differential regulation of levels of nicotinic receptor subunit transcripts in adult sympathetic neurons after axotomy. J Neurobiol. 1998 Feb 5; 34(2):164-178.
  29. Fyodorov D, Nelson T, Deneris E. (1998)
    Pet-1, a novel ETS domain factor that can activate neuronal nAchR gene transcription. J Neurobiol. 1998 Feb 5; 34(2):151-163.
  30. McDonough J, Deneris E. (1997)
    beta43': An enhancer displaying neural-restricted activity is located in the 3'-untranslated exon of the rat nicotinic acetylcholine receptor beta4 gene. J Neurosci. 1997 Apr 1; 17(7):2273-2283.
  31. Yang X, Yang F, Fyodorov D, Wang F, McDonough J, Herrup K, Deneris E. (1997)
    Elements between the protein-coding regions of the adjacent beta 4 and alpha 3 acetylcholine receptor genes direct neuron-specific expression in the central nervous system. J Neurobiol. 1997 Mar; 32(3):311-324.
  32. Fyodorov D, Deneris E. (1996)
    The POU domain of SCIP/Tst-1/Oct-6 is sufficient for activation of an acetylcholine receptor promoter. Mol Cell Biol. 1996 Sep; 16(9):5004-5014.
  33. Yang X, Fyodorov D, Deneris ES. (1995)
    Transcriptional analysis of acetylcholine receptor alpha 3 gene promoter motifs that bind Sp1 and AP2. J Biol Chem. 1995 Apr 14; 270(15):8514-8520.
  34. Yang X, McDonough J, Fyodorov D, Morris M, Wang F, Deneris ES. (1994)
    Characterization of an acetylcholine receptor alpha 3 gene promoter and its activation by the POU domain factor SCIP/Tst-1. J Biol Chem. 1994 Apr 8; 269(14):10252-10264.
faculty/deneris/index.txt · Last modified: 2015/10/06 13:12 by hxm8