- Assistant Professor
The research in my laboratory is currently focused on two major areas. The first area explores the early events of neurotrophin receptor activation and their effects on neural stem cells and the second explores the biological mechanisms involved in the maintenance and differentiation of neural stem cells.
Neurotrophins and trk mediated signaling
The NGF family of growth factors mediate their effects through the trk family of receptor tyrosine kinase and through p75 a member of the TNF family of receptors. Neurotrophins induce the receptors to dimerize.
Following dimerization, the receptors autophosphorylate on specific tyrosine residues that serve as docking sites for other signaling molecules that initiate several signaling cascades, leading to the activation of different key proteins important for biological responses. We are using new visualization techniques to map the dynamic interactions of the receptors and signaling molecules and their trafficking in vivo. Additional ongoing projects include the role that neurotrophins have on the regeneration of specific nerve tracks in spinal cord injury.
Maintanance and differentiation of neural stem cells
We are investigating how cell fate is controlled by intrinsic and exogenous factors and which molecules are involved in maintaining the stem cell characteristics. Our laboratory uses several approaches including in vitro and in vivo techniques to manipulate the expression of molecules that act as dominant negative or constitutively active. We are taking advantage of techniques such as microarray analysis and subtractive hybridization to isolate genes involved at different stages of stem cell differentiation.
1: Enzmann GU, Benton RL, Woock JP, Howard RM, Tsoulfas P, Whittemore SR.
Abstract Consequences of noggin expression by neural stem, glial, and neuronal precursor cells engrafted into the injured spinal cord.
Exp Neurol. 2005 Oct;195(2):293-304.
PMID: 16087174 [PubMed - indexed for MEDLINE]
2: Cao Q, Xu XM, Devries WH, Enzmann GU, Ping P, Tsoulfas P, Wood PM, Bunge MB, Whittemore SR.
Free Full Text Functional recovery in traumatic spinal cord injury after transplantation of multineurotrophin-expressing glial-restricted precursor cells.
J Neurosci. 2005 Jul 27;25(30):6947-57.
PMID: 16049170 [PubMed - indexed for MEDLINE]
3: Mammolenti M, Gajavelli S, Tsoulfas P, Levy R.
Free Full Text Absence of major histocompatibility complex class I on neural stem cells does not permit natural killer cell killing and prevents recognition by alloreactive cytotoxic T lymphocytes in vitro.
Stem Cells. 2004;22(6):1101-10.
PMID: 15536199 [PubMed - indexed for MEDLINE]
4: Baez JC, Gajavelli S, Thomas CK, Grumbles RM, Aparicio B, Byer D, Tsoulfas P.
Abstract Embryonic cerebral cortex cells retain CNS phenotypes after transplantation into peripheral nerve.
Exp Neurol. 2004 Oct;189(2):422-5.
PMID: 15380492 [PubMed - indexed for MEDLINE]
5: Gajavelli S, Wood PM, Pennica D, Whittemore SR, Tsoulfas P.
Abstract BMP signaling initiates a neural crest differentiation program in embryonic rat CNS stem cells.
Exp Neurol. 2004 Aug;188(2):205-23.
PMID: 15246821 [PubMed - indexed for MEDLINE]
6: Castellanos DA, Tsoulfas P, Frydel BR, Gajavelli S, Bes JC, Sagen J.
Abstract TrkC overexpression enhances survival and migration of neural stem cell transplants in the rat spinal cord.
Cell Transplant. 2002;11(3):297-307.
PMID: 12075995 [PubMed - indexed for MEDLINE]
7: Plum LA, Parada LF, Tsoulfas P, Clagett-Dame M.
Free Full Text Retinoic acid combined with neurotrophin-3 enhances the survival and neurite outgrowth of embryonic sympathetic neurons.
Exp Biol Med (Maywood). 2001 Sep;226(8):766-75.
PMID: 11520943 [PubMed - indexed for MEDLINE]
8: Cao QL, Zhang YP, Howard RM, Walters WM, Tsoulfas P, Whittemore SR.
Abstract Pluripotent stem cells engrafted into the normal or lesioned adult rat spinal cord are restricted to a glial lineage.
Exp Neurol. 2001 Jan;167(1):48-58.
PMID: 11161592 [PubMed - indexed for MEDLINE]
9: Lin MI, Das I, Schwartz GM, Tsoulfas P, Mikawa T, Hempstead BL.
Abstract Trk C receptor signaling regulates cardiac myocyte proliferation during early heart development in vivo.
Dev Biol. 2000 Oct 15;226(2):180-91.
PMID: 11023679 [PubMed - indexed for MEDLINE]
10: O'Connell L, Hongo JA, Presta LG, Tsoulfas P.
Free Full Text TrkA amino acids controlling specificity for nerve growth factor.
J Biol Chem. 2000 Mar 17;275(11):7870-7.
PMID: 10713102 [PubMed - indexed for MEDLINE]
11: Vicario-Abejon C, Collin C, Tsoulfas P, McKay RD.
Abstract Hippocampal stem cells differentiate into excitatory and inhibitory neurons.
Eur J Neurosci. 2000 Feb;12(2):677-88.
PMID: 10712648 [PubMed - indexed for MEDLINE]
12: Panchision DM, Martin-DeLeon PA, Takeshima T, Johnston JM, Shimoda K, Tsoulfas P, McKay RD, Commissiong JW.
Abstract An immortalized, type-1 astrocyte of mesencephalic origin source of a dopaminergic neurotrophic factor.
J Mol Neurosci. 1998 Dec;11(3):209-21.
PMID: 10344791 [PubMed - indexed for MEDLINE]
13: Urfer R, Tsoulfas P, O'Connell L, Hongo JA, Zhao W, Presta LG.
Free Full Text High resolution mapping of the binding site of TrkA for nerve growth factor and TrkC for neurotrophin-3 on the second immunoglobulin-like domain of the Trk receptors.
J Biol Chem. 1998 Mar 6;273(10):5829-40.
PMID: 9488719 [PubMed - indexed for MEDLINE]
14: Tessarollo L, Tsoulfas P, Donovan MJ, Palko ME, Blair-Flynn J, Hempstead BL, Parada LF.
Free in PMC Targeted deletion of all isoforms of the trkC gene suggests the use of alternate receptors by its ligand neurotrophin-3 in neuronal development and implicates trkC in normal cardiogenesis.
Proc Natl Acad Sci U S A. 1997 Dec 23;94(26):14776-81.
PMID: 9405689 [PubMed - indexed for MEDLINE]
15: Dechant G, Tsoulfas P, Parada LF, Barde YA.
Free Full Text The neurotrophin receptor p75 binds neurotrophin-3 on sympathetic neurons with high affinity and specificity.
J Neurosci. 1997 Jul 15;17(14):5281-7.
PMID: 9204912 [PubMed - indexed for MEDLINE]
16: Urfer R, Tsoulfas P, O'Connell L, Presta LG.
Abstract Specificity determinants in neurotrophin-3 and design of nerve growth factor-based trkC agonists by changing central beta-strand bundle residues to their neurotrophin-3 analogs.
Biochemistry. 1997 Apr 22;36(16):4775-81.
PMID: 9125498 [PubMed - indexed for MEDLINE]
17: Tsoulfas P, Stephens RM, Kaplan DR, Parada LF.
Free Full Text TrkC isoforms with inserts in the kinase domain show impaired signaling responses.
J Biol Chem. 1996 Mar 8;271(10):5691-7.
PMID: 8621434 [PubMed - indexed for MEDLINE]
18: Donovan MJ, Miranda RC, Kraemer R, McCaffrey TA, Tessarollo L, Mahadeo D, Sharif S, Kaplan DR, Tsoulfas P, Parada L, et al.
Abstract Neurotrophin and neurotrophin receptors in vascular smooth muscle cells. Regulation of expression in response to injury.
Am J Pathol. 1995 Aug;147(2):309-24.
PMID: 7639328 [PubMed - indexed for MEDLINE]
19: Urfer R, Tsoulfas P, O'Connell L, Shelton DL, Parada LF, Presta LG.
Free in PMC An immunoglobulin-like domain determines the specificity of neurotrophin receptors.
EMBO J. 1995 Jun 15;14(12):2795-805.
PMID: 7796806 [PubMed - indexed for MEDLINE]
20: Offenhauser N, Bohm-Matthaei R, Tsoulfas P, Parada L, Meyer M.
Abstract Developmental regulation of full-length trkC in the rat sciatic nerve.
Eur J Neurosci. 1995 May 1;7(5):917-25. Erratum in: Eur J Neurosci 1995 Sep 1;7(9):2005.
PMID: 7613627 [PubMed - indexed for MEDLINE]
21: Urfer R, Tsoulfas P, Soppet D, Escandon E, Parada LF, Presta LG.
Free in PMC The binding epitopes of neurotrophin-3 to its receptors trkC and gp75 and the design of a multifunctional human neurotrophin.
EMBO J. 1994 Dec 15;13(24):5896-909.
PMID: 7529173 [PubMed - indexed for MEDLINE]
22: Donovan MJ, Hempstead B, Huber LJ, Kaplan D, Tsoulfas P, Chao M, Parada L, Schofield D.
Abstract Identification of the neurotrophin receptors p75 and trk in a series of Wilms' tumors.
Am J Pathol. 1994 Oct;145(4):792-801.
PMID: 7943171 [PubMed - indexed for MEDLINE]
23: Averbuch-Heller L, Pruginin M, Kahane N, Tsoulfas P, Parada L, Rosenthal A, Kalcheim C.
Free in PMC Neurotrophin 3 stimulates the differentiation of motoneurons from avian neural tube progenitor cells.
Proc Natl Acad Sci U S A. 1994 Apr 12;91(8):3247-51.
PMID: 8159733 [PubMed - indexed for MEDLINE]
24: Lindholm D, Castren E, Tsoulfas P, Kolbeck R, Berzaghi Mda P, Leingartner A, Heisenberg CP, Tessarollo L, Parada LF, Thoenen H.
Free Full Text Neurotrophin-3 induced by tri-iodothyronine in cerebellar granule cells promotes Purkinje cell differentiation.
J Cell Biol. 1993 Jul;122(2):443-50. Erratum in: J Cell Biol 1998 Dec 28;143(7):following 2090. Tesarollo, L [corrected to Tessarollo, L].
PMID: 8320266 [PubMed - indexed for MEDLINE]
25: Tessarollo L, Tsoulfas P, Martin-Zanca D, Gilbert DJ, Jenkins NA, Copeland NG, Parada LF.
Free Full Text trkC, a receptor for neurotrophin-3, is widely expressed in the developing nervous system and in non-neuronal tissues.
Development. 1993 Jun;118(2):463-75. Erratum in: Development 1993 Aug;118(4):following 1384.
PMID: 8223273 [PubMed - indexed for MEDLINE]
26: Tsoulfas P, Soppet D, Escandon E, Tessarollo L, Mendoza-Ramirez JL, Rosenthal A, Nikolics K, Parada LF.
Abstract The rat trkC locus encodes multiple neurogenic receptors that exhibit differential response to neurotrophin-3 in PC12 cells.
Neuron. 1993 May;10(5):975-90.
PMID: 8494648 [PubMed - indexed for MEDLINE]
27: Parada LF, Tsoulfas P, Tessarollo L, Blair J, Reid SW, Soppet D.
Abstract The Trk family of tyrosine kinases: receptors for NGF-related neurotrophins.
Cold Spring Harb Symp Quant Biol. 1992;57:43-51.
PMID: 1339678 [PubMed - indexed for MEDLINE]
28: Tian SS, Tsoulfas P, Zinn K.
Abstract Three receptor-linked protein-tyrosine phosphatases are selectively expressed on central nervous system axons in the Drosophila embryo.
Cell. 1991 Nov 15;67(4):675-80.
PMID: 1657402 [PubMed - indexed for MEDLINE]
29: Buvoli M, Biamonti G, Tsoulfas P, Bassi MT, Ghetti A, Riva S, Morandi C.
Free in PMC cDNA cloning of human hnRNP protein A1 reveals the existence of multiple mRNA isoforms.
Nucleic Acids Res. 1988 May 11;16(9):3751-70.
PMID: 2836799 [PubMed - indexed for MEDLINE]
30: Riva S, Morandi C, Tsoulfas P, Pandolfo M, Biamonti G, Merrill B, Williams KR, Multhaup G, Beyreuther K, Werr H, et al.
Free in PMC Mammalian single-stranded DNA binding protein UP I is derived from the hnRNP core protein A1.
EMBO J. 1986 Sep;5(9):2267-73.
PMID: 3023065 [PubMed - indexed for MEDLINE]