Curriculum Vitae
AB Cornell University 1975
Ph.D. Caltech 1980
Postdoctorate: Neurobiology (with NC Spitzer) UCSD 1980-83
Postdoctorate Neurobiology (with LF Reichardt) UCSF 1983-86
Research Assistant Professor, HHMI, UCSF 1986-88
Assistant Professor at UM 1988-93
Associate Professor at UM 1993-97
Professor at UM 1997-present
Director, UM Neuroscience Center, 2001-present
Associate Dean for Graduate Studies 2007-present
Research Interests
Our lab is broadly interested in the development and regeneration of the nervous system; in particular, we are focused on signaling processes underlying axon growth and guidance during development, and on the mechanisms underlying sprouting and regeneration after CNS injury. We have two main lines of inquiry.
First, we are studying the biological function, ligand-receptor interactions, physiological substrates, and transduction mechanisms of receptor protein tyrosine phosphatases (RPTPs). This group of about 20 proteins comprises transmembrane enzymes with extracellular domains like those of cell adhesion molecules (CAMs), and intracellular domains that negatively regulate tyrosine phosphorylation, activating or inhibiting a wide variety of signaling proteins. We are particularly interested in the CAM-like type IIa and type III RPTPs. We have recently, for example, identified a novel protein (NPCD) that is a substrate for the type III RPTP, PTPRO, and we are studying its expression and function to learn how it acts to coordinate neuronal signals.
Our other research area involves strategies to understand and manipulate regulatory mechanisms underlying the control of axonal regeneration after injury to the central nervous system. This work is in collaboration with Dr. Vance Lemmon, and has two main directions. First, we are screening a novel chemical compound library (and following up hits we have developed) for compounds that can overcome inhibitory signals in the injured CNS. We have identified several novel chemical compounds that can overcome inhibitory signals from CNS myelin and from inhibitory chondroitin sulfate proteoglycans, and we are studying their mechanisms of action. Second, we are using high content screening together with subtractive, microarray, and bioinformatics strategies to identify genes that can promote or inhibit axonal regeneration.
 |
| The Lemmon/Bixby Lab: February 2005 |
More Photos: Neuroscience Program Retreat 2002
Major Research Projects
Personnel: John L. Bixby, Ph.D. (PI)
Postdocs: Stephanie Bingham, Ph.D., Lynn Usher, Ph.D., Alexis Tapanes-Castillo, Ph.D.
Graduate Students: Amy Hower, Andrea Peterson, Andrew Tseng
Technical staff: Xuan Le, Dinara Strikis, Yan Shi
Collaborators: Vance Lemmon, Ph.D., Frank Longo, M.D., Ph.D., Mary Bunge, Ph.D., Jeff Goldberg, M.D., Ph.D., Caitlin Hill, Ph.D., Yuanli Duan, Ph.D., Manny Gonzalez-Brito, D.O.
1) Functions and Binding Properties of Receptor Tyrosine Phosphatases
The regulation of tyrosine phosphorylation is critical in the growth and guidance of axons during the development of the vertebrate nervous system. Accumulating evidence suggests that receptor-type tyrosine phosphatases (RPTPs) play key roles in the signaling processes underlying axon growth. Several classes of RPTP possess extracellular domains (ECDs) that are structurally similar to those of cell adhesion molecules (CAMs). Our overall hypothesis is that these CAM-like RPTPs, which are expressed on the surfaces of developing neurons, are involved both as regulatory ligands and as neuronal receptors in the regulation of vertebrate axon growth. Our lab has established that 2 vertebrate RPTPs, PTPRD and PTPRO, are involved in axon growth regulation. These are members of 2 different families of RPTPs: type IIa (PTPRD) and type III (PTPRO). We are currently working on a number of projects relating to the regulation, substrates, ligand-receptor interactions, and in vivo functions of these classes of RPTP.
1. Characterize ligand/receptor interactions for PTPRD and PTPRO. PTPRD is a homophilic cell adhesion molecule. We are examining the extent to which homophilic binding can explain the functional activities of PTPRD, and searching for additional ligands/receptors. PTPRO has no known ligands or receptors. We are taking a variety of approaches to identify and characterize functionally important PTPRO binding proteins.
2. Characterize the expression and function of a novel PTPRO substrate, neuronal pentraxin with chromo domain (NPCD). NPCD is unique among known proteins in possessing both a chromo domain and a neuronal pentraxin domain. We are characterizing its interactions and functional activities in neurons. We have two distinct mutant mouse lines that will facilitate these studies.
3. Characterize the in vivo functions of PTPRO and the PTPRD paralog, LAR. We are using PTPRO and PTPRO/LAR ko mice to examine the roles of these proteins in neuronal development. We have found that PTPRO and LAR cooperate to regulate sensory neuron differentiation during development, and are also focusing on motor and visual systems.
4. Characterize the regulation of RPTP activity by dimerization. We are using biochemical techniques in cultured cells to determine how ligand binding and oligomerization regulate functional activities of type IIa and type III RPTPs (PTPRO, PTPRJ, PTPRD).
 |
| Expression of NPCD (red) and PTPRO (green) in hippocampus (A-C) and kidney (D-F). |
2) Strategies for Promoting Regeneration After CNS Injury
Axons do not regenerate after injury to the brain or spinal cord. One major barrier to regeneration is the presence in the injured CNS of growth-inhibitory proteins of glial origin (myelin and proteins associated with the “glial scar”). A second hurdle is there is an intrinsic program of “regeneration-associated genes” (RAGs) turned on in peripheral neurons after injury, and that this program fails to be induced in injured CNS neurons. In collaboration with Dr. Vance Lemmon, we are taking two complementary approaches to understanding and alleviating these problems.
1. We have begun a phenotype-based high-content screen of a chemical compound library chosen for its flexibility and chemical properties. The screen is based on the ability of chemical compounds to increase neurite outgrowth from CNS neurons challenged with inhibitory myelin substrates. Our initial screen of 312 compounds has produced 4 lead [leed] compounds capable of strongly increasing neurite growth of cerebellar neurons on inhibitory substrates (myelin and proteoglycans). Secondary experiments have shown that these compounds act on a variety of CNS neuronal types, including mature neurons, and that they can overcome inhibition present in a model of the glial scar. Thus, these are very promising compounds. Our immediate goals for these compounds are to characterize their activities in various in vivo models of injury (optic nerve injury, spinal cord injury, traumatic brain injury), and to identify their molecular targets and mechanisms of action. We will also continue the screen of this novel library to identify more such promising compounds.
2. We are taking various approaches to identifying genes involved in axonal regeneration. A variety of strategies targeting the inhibitory environment of the injured CNS have demonstrated that while manipulations can improve regeneration, the vast majority of supraspinal neurons (>95%) still fail to regenerate axons. Thus, once inhibition has been cleared, neurons themselves must be activated to regenerate into the now-permissive environment. We hypothesize that this involves expression of an appropriate suite of regeneration-associated genes. We are using subtraction hybridization as well as various bioinformatics approaches to develop a list of potential regeneration-associated genes. We have also developed high-throughput approaches to neuronal transfection and “high-content screening” of primary nerve cells so that we can use overexpression and shRNA knockdown approaches to identify the genes on our list that are functionally active.
 |
| Automated tracing of neurons and axons. Computer tracing (B) of image from automated microscope (A). |
Recent Publications
Bixby, J.L., Baerwald, K.L., Wang, C., Rathjen, F.G., and Ruegg, M.A. (2002). A neuronal inhibitory domain in the N-terminal half of agrin, J. Neurobiol. 50: 164-179.
Chen, B., Perron, J., Hammonds-Odie, L., Masters, B., and Bixby, J.L. (2002). SHP-2 mediates target-controlled axonal branching and NGF-dependent neurite growth in sympathetic neurons. Dev. Biol. 252: 170-187.
Beltran, P.J., and Bixby, J.L. (2003). Receptor protein tyrosine phosphatases as mediators of cellular adhesion. Frontiers in Bioscience 8: d87-99.
Beltran, P.J., Bixby, J.L., and Masters, B.A. (2003). Expression of PTPRO during mouse development suggests involvement in axonogenesis and in differentiation of NT-3 and NGF-dependent neurons. J. Comp. Neurol. 456: 384-395.
Baerwald de la Torre, K., Winzen, U., Halfter, W., and Bixby, J.L. (2004). Glycosaminoglycan-dependent and -independent inhibition of neurite outgrowth by agrin. J. Neurochem. 90: 50-61.
Ernsberger, U., Esposito, L., Partimo, S., Huber, K., Franke, A., Bixby, J.L., Kalcheim, C., and Unsicker, K. (2005). Expression of neuronal markers suggests heterogeneity of chick sympathoadrenal cells prior to invasion of the adrenal anlagen. Cell & Tissue Research 319: 1-13.
Chen, B., and Bixby, J.L. (2005). NPCD (neuronal pentraxin with chromo domain) is a novel class of protein expressed in multiple neuronal domains. J. Comp. Neurol. 481: 391-402.
Chen, B., and Bixby, J.L. (2005). A novel substrate of receptor tyrosine phosphatase PTPRO is required for NGF-induced process outgrowth. J. Neuroscience 25:880-888.
Dimitropoulou, A., and Bixby, J.L. (2005). Motor neurite outgrowth is selectively inhibited by cell surface MuSK and agrin. Molecular & Cellular Neuroscience 28: 292-302.
Stepanek, L., Stoker, A.W., Stoeckli, E., and Bixby, J.L. (2005). Receptor tyrosine phosphatases guide vertebrate motor axons during development. J. Neuroscience 25: 3813 - 23.
Buchser WJ, Pardinas JR, Shi Y, Bixby JL, Lemmon V. (2006). Efficient and inexpensive 96-well electroporation method for transfection of mammalian central neurons. BioTechniques 41:619-24.
Gonzalez-Brito, M., and Bixby, J.L. (2006). Differential activities in adhesion and neurite growth of fibronectin type III repeats in the PTP- d extracellular domain. Intl. J. Dev. Neurosci. 24(7):425-9.
|
