- Associate Professor
Our overall goal is to achieve a better understanding of how the CNS develops and regenerates following injury and disease. We have focused on a family of molecules, ephrins and Eph receptors, since they have been shown to have a dynamic influence in regulating developmental functions, including axonal growth and guidance, synaptic formation and function, angiogenesis, bone morphogenesis, and neurogenesis. We believe that studying the developing nervous systems can provide important insight to mechanisms that would regulate regeneration after injury. A choice tool in my laboratory are gene-targeted knockout mice, where alterations in CNS develop can provide an understanding of gene functions. We also attempt to take a comprehensive approach to each of our experimental goals, which include molecular, biochemical, genetic, cellular, behavioral, and physiological analyzes. We believe that a well-rounded approach to anyone question will provide a better understanding of gene function. The goals of my laboratory are divided into three areas:
(1) Neurogenesis: We have recently demonstrated new and novel functions for ephrins and Eph receptors in adult neurogenesis, where they function to maintain proper stem/progenitor cell and neuroblast numbers by regulating proliferation and survival. Current studies are continuing to dissect the mechanisms involved in these studies. In addition, we are employing high-throughput methods of siRNA knockdown to examine potential intracellular signaling intermediates that may participate in these functions. We are complementing these studies by examining whether ephrins and Eph receptors regulated endogenous or transplanted stem cell functions after traumatic brain or spinal cord injury.
(2) Axon growth and guidance: Ephrins and Eph receptors are well known for their role in regulating growth and guidance, classically through repulsion of developing growth cones. Our indepth studies have extended our knowledge on the molecules that control forebrain midline pathfinding, and found that also function to attract developing growth cones. There are dynamic choice point cues on the developing CNS midline that signal a axon to either cross or not cross the midline. We have determined that the family of ephrins and Eph receptors play a significant role in this choice determination, and genetic analysis has shown that there is a complex interplay between the role of growth and guidance molecules on both the growing axon sprout and the positioning of the local guideposts. When ephrins and/or Eph receptors are absent (i.e. knockout mice) corpus callosum axons fail to transverse the CNS midline, and instead form swirls of axon bundles called Probst's bundles. In human, corpus callosum defects are found in many disorders and syndromes. We are currently investigating whether individual ephrins and Eph receptors map to specific chromosomal disease regions with the hope to identify the genetic basis for CNS defects associated with these diseases. As well, we are continuing to employ animal models to examine the molecular mechanism by which these molecules regulate these events.
(3) Synaptic formation and function: Ephrins and Eph receptors are known to regulate the synaptic formation and efficacy in the developing brain. We are extending our findings to investigate three different questions: (a) How ephrins and Eph receptor regulate NMDA receptor levels in the synaptic membrane?; (b) What role ephrins and Eph receptor have in glia-neural interactions and how they affect synaptic formation and function?; (c) What role ephrins and Eph receptor play on synaptic function after traumatic brain injury? Understanding these functions will better enable us to investigate how regenerating axons can form functional contacts after injury.
In summary, our studies evaluate all aspects of the neuronal life from early stem cell differentiation to axonal growth to synaptic formation and function to cell death and injury. We hope to improve basic understanding of the mechanisms involved as well as develop therapeutic strategies to promote recovery. Our long-term goal for all these projects are to develop strategies that will lead to clinical trials and patient recovery.
1: Ricard J, Salinas J, Garcia L, Liebl DJ.
Abstract EphrinB3 regulates cell proliferation and survival in adult neurogenesis.
Mol Cell Neurosci. 2006 Feb 14; [Epub ahead of print]
PMID: 16483793 [PubMed - as supplied by publisher]
2: Rodenas-Ruano A, Perez-Pinzon MA, Green EJ, Henkemeyer M, Liebl DJ.
Abstract Distinct roles for ephrinB3 in the formation and function of hippocampal synapses.
Dev Biol. 2006 Feb 6; [Epub ahead of print]
PMID: 16466709 [PubMed - as supplied by publisher]
3: Mendes SW, Henkemeyer M, Liebl DJ.
Abstract Multiple Eph receptors and B-class ephrins regulate midline crossing of corpus callosum fibers in the developing mouse forebrain.
J Neurosci. 2006 Jan 18;26(3):882-92.
PMID: 16421308 [PubMed - indexed for MEDLINE]
4: Blits-Huizinga CT, Nelersa CM, Malhotra A, Liebl DJ.
Abstract Ephrins and their receptors: binding versus biology.
IUBMB Life. 2004 May;56(5):257-65. Review.
PMID: 15370889 [PubMed - indexed for MEDLINE]
5: Ricard J, Liebl DJ.
Abstract Neurogenesis: is the adult stem cell young or old?
IUBMB Life. 2004 Jan;56(1):1-6. Review.
PMID: 14992373 [PubMed - indexed for MEDLINE]
6: Simpson PJ, Wang E, Moon C, Matarazzo V, Cohen DR, Liebl DJ, Ronnett GV.
Abstract Neurotrophin-3 signaling maintains maturational homeostasis between neuronal populations in the olfactory epithelium.
Mol Cell Neurosci. 2003 Dec;24(4):858-74.
PMID: 14697654 [PubMed - indexed for MEDLINE]
7: Howard MA, Rodenas-Ruano A, Henkemeyer M, Martin GK, Lonsbury-Martin BL, Liebl DJ.
Abstract Eph receptor deficiencies lead to altered cochlear function.
Hear Res. 2003 Apr;178(1-2):118-30.
PMID: 12684184 [PubMed - indexed for MEDLINE]
8: Liebl DJ, Morris CJ, Henkemeyer M, Parada LF.
Abstract mRNA expression of ephrins and Eph receptor tyrosine kinases in the neonatal and adult mouse central nervous system.
J Neurosci Res. 2003 Jan 1;71(1):7-22.
PMID: 12478610 [PubMed - indexed for MEDLINE]
9: Simpson PJ, Miller I, Moon C, Hanlon AL, Liebl DJ, Ronnett GV.
Free Full Text Atrial natriuretic peptide type C induces a cell-cycle switch from proliferation to differentiation in brain-derived neurotrophic factor- or nerve growth factor-primed olfactory receptor neurons.
J Neurosci. 2002 Jul 1;22(13):5536-51.
PMID: 12097505 [PubMed - indexed for MEDLINE]
10: Liebl DJ, Huang W, Young W, Parada LF.
Abstract Regulation of Trk receptors following contusion of the rat spinal cord.
Exp Neurol. 2001 Jan;167(1):15-26.
PMID: 11161589 [PubMed - indexed for MEDLINE]
11: Kernie SG, Liebl DJ, Parada LF.
Free in PMC BDNF regulates eating behavior and locomotor activity in mice.
EMBO J. 2000 Mar 15;19(6):1290-300.
PMID: 10716929 [PubMed - indexed for MEDLINE]
12: Liebl DJ, Klesse LJ, Tessarollo L, Wohlman T, Parada LF.
Free in PMC Loss of brain-derived neurotrophic factor-dependent neural crest-derived sensory neurons in neurotrophin-4 mutant mice.
Proc Natl Acad Sci U S A. 2000 Feb 29;97(5):2297-302.
PMID: 10681461 [PubMed - indexed for MEDLINE]
13: Liebl DJ, Mbiene JP, Parada LF.
Abstract NT4/5 mutant mice have deficiency in gustatory papillae and taste bud formation.
Dev Biol. 1999 Sep 15;213(2):378-89.
PMID: 10479455 [PubMed - indexed for MEDLINE]
14: Hu YQ, Liebl DJ, Dluzen DE, Koo PH.
Abstract Inhibition of dopamine and choline acetyltransferase concentrations in rat CNS neurons by rat alpha 1- and alpha 2-macroglobulins.
J Neurosci Res. 1998 Feb 15;51(4):541-50.
PMID: 9514208 [PubMed - indexed for MEDLINE]
15: Liebl DJ, Tessarollo L, Palko ME, Parada LF.
Free Full Text Absence of sensory neurons before target innervation in brain-derived neurotrophic factor-, neurotrophin 3-, and TrkC-deficient embryonic mice.
J Neurosci. 1997 Dec 1;17(23):9113-21.
PMID: 9364058 [PubMed - indexed for MEDLINE]
16: Koo PH, Liebl DJ, Qiu WS, Hu YQ, Dluzen DE.
No abstract Monoamine-activated alpha 2-macroglobulin inhibits neurite outgrowth, survival, choline acetyltransferase, and dopamine concentration of neurons by blocking neurotrophin-receptor (trk) phosphorylation and signal transduction.
Ann N Y Acad Sci. 1994 Sep 10;737:460-4. No abstract available.
PMID: 7524422 [PubMed - indexed for MEDLINE]
17: Liebl DJ, Koo PH.
Abstract Monoamine-activated alpha 2-macroglobulin inhibits choline acetyltransferase of embryonic basal forebrain neurons and reversal of the inhibition by NGF and BDNF but not NT-3.
J Neurosci Res. 1994 Jul 1;38(4):407-14.
PMID: 7523691 [PubMed - indexed for MEDLINE]
18: Liebl DJ, Koo PH.
Abstract Comparative binding of neurotrophins (NT-3, CNTF and NGF) and various cytokines to alpha 2-macroglobulin.
Biochem Biophys Res Commun. 1993 Jun 30;193(3):1255-61.
PMID: 7686751 [PubMed - indexed for MEDLINE]
19: Liebl DJ, Koo PH.
Abstract Serotonin-activated alpha 2-macroglobulin inhibits neurite outgrowth and survival of embryonic sensory and cerebral cortical neurons.
J Neurosci Res. 1993 Jun 1;35(2):170-82.
PMID: 7686585 [PubMed - indexed for MEDLINE]
20: Koo PH, Liebl DJ.
Abstract Inhibition of nerve growth factor-stimulated neurite outgrowth by methylamine-modified alpha 2-macroglobulin.
J Neurosci Res. 1992 Apr;31(4):678-92.
PMID: 1374478 [PubMed - indexed for MEDLINE]
21: Wang-Bennett LT, Liebl DJ, Bennett GN.
Abstract Targeted neuronal lesion induced by photosensitizing dyes.
Brain Res. 1990 Nov 26;534(1-2):122-8.
PMID: 1705848 [PubMed - indexed for MEDLINE]