Faculty Book
DANIEL J. LIEBL, Ph.D.
Associate Professor, Neurological Surgery
Function of growth and guidance molecules in the developing and regenerating nervous systems
Research
Interests
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.
Video Introduction
Petit A., Kennedy TE, Sellers DL, Liebl DJ, Tessier-Lavigne M, Horner PJ. Adult spinal cord progenitor cells are repelled by netrin-1 in the embryonic and injured adult spinal cord. PNAS, In press (2007).
Shembade, N, Harhay, NS, Liebl DJ, Harhaj, EW.Essential role for TAX1BP1 in the termination of TNF-a, IL-1 and LPS-mediated NF-kB and JNK signaling. EMBO, 26(17):3910-22 (2007).
Ricard J, Salinas J, Garcia L, Liebl DJ.EphrinB3 Regulates Cell Proliferation and Survival in Adult Neurogenesis. Mol Cell Neurosci, 31:713-722 (2006).
Rodenas-Ruano A, Perez-Pinzon M, Green EJ, Henkemeyer M, Liebl DJ.Distinct roles for ephrinB3 in the formation and function of hippocampal synapses. Dev Biology, 292(1):34-45 (2006).
Mendes SW, Henkemeyer M, Liebl DJ.Multiple Eph receptors and B-class ephrins regulate midline crossing of corpus callosum fibers in the developing mouse forebrain. J Neurosci, 26(3):882-892 (2006).2 (2006).
Blitz-Huzinga C, Nelersa CM, Malhotra A, Liebl DJ. (2004) Ephrins and their receptors: Binding versus Biology. IUBMB Life. 56(5) 257-265.
Ricard J and Liebl DJ (2004) Neurogenesis: Is the adult stem cell young of old? IUBMB Life. 56(1): 1-6.
Kernie SG*, Liebl* DJ, Parada LF (2000) BDNF regulates eating behavior and locomotor activity in mice. EMBO 19(6):1290-2000.
Liebl DJ, Klesse LJ, Tessarollo L, Waldman T, Parada LF (2000) Loss of BDNF-dependent neural crest derived sensory neurons in NT-4/5 mutant mice. PNAS 97(5):2297-2302.
Liebl DJ, Tessarollo L, Palk ME, Parada LF (1997) Absence of sensory neurons prior to target innervation in BDNF, NT-3 & TrkC deficient embryonic mice. J Neurosci 17:9113-9121.
Last updated: October, 2007
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