University of Zurich, Switzerland, Ph.D. 1995 Biochemistry
Netherlands Institute for Brain Research, Postdoc. 1995-1997, Neuroscience
Johns Hopkins University, Baltimore MD, Postdoc. 1997-2001, Neuroscience
University of Rochester NY, Assistant professor 2002-2007
University of Michigan, Associate Professor 2008-2014
University of Michigan, Professor, 2015
I have a long standing interest in understanding the molecular and cellular mechanisms that regulate axo-glial interactions in CNS health and disease. I am particularly interested in glial signals that control axon growth and stability, and conversely, neuronal signals that influence myelin development and repair. Ongoing research in my laboratory is using a broad spectrum of techniques to study molecularmechanisms of axo-glial interactions.
Mechanisms of axonal growth inhibition: The regenerative capacity of injured adult mammalian central nervous system (CNS) tissue is very limited. Disease or injury that causes destruction or damage to neuronal networks typically results in permanent neurological deficits. Injury to brain or spinal cord often leads to transection or shearing of vital fiber tracts. Multiple lines of evidence suggest that the growth inhibitory nature of injured adult CNS tissue is a major barrier to regenerative growth of severed axons. We pursue a mouse genetic approach to study the function of different classes of proteins that are known to regulate neuronal growth, including members of the Semaphorin family and their cognate receptors (Neuropilins and Plexins). Our more recent studies are focusing on myelin-associated inhibitors (MAIs) and their receptors. The Nogo Receptors NgR1 and NgR2 have been implicated in regulating acute neuronal responses to the myelin inhibitors Nogo/RTN4, Myelin-Associated Glycoprotein (MAG), and Oligodendrocyte-Myelin Glycoprotein (OMgp). We recently identified NgR1 and NgR3 as novel receptors for inhibitory chondroitin sulfate proteoglycans (CSPGs). Loss of NgR family members individually is not sufficient to overcome CSPG inhibition; however, the combined loss of NgR1 and NgR3 leads to a significant release of CSPG inhibition. In NgR123–/– triple mutants, severed retinal ganglion cell (RGC) axons show enhanced regenerative growth. Interestingly, NgR13–/–, but not NgR12–/– double mutants, phenocopy the optic nerve regeneration phenotype of NgR123–/– mice. A further enhancement of axon regeneration is observed in NgR13/RPTPσ triple mutants, revealing a genetic interaction among NgR family members and the previously identified CSPG receptor RPTPσ. Our studies provide unexpected evidence for shared receptor mechanisms for “prototypic myelin inhibitors” and CSPGs, two major classes of growth inhibitory molecules abundant in the adult mammalian CNS. We are currently developing soluble receptor antagonists to block the myelin and CSPG inhibitory effects toward neurons in vitro, if such antagonists can be developed, they will be tested for their therapeutic efficacy following CNS injury in vivo.
Negative regulators of synaptic plasticity: Many human brain disorders, including various forms of mental retardation, schizophrenia and autism, are correlated with changes in the number of synapses or are believed to be caused by an imbalance between neuronal excitation and inhibition. Thus, understanding how neuronal structure and synaptic function are regulated may provide key insights into the molecular mechanisms that govern synaptic development, plasticity, and ultimately, how the deregulation of these processes leads to neurological diseases. Nogo receptors and their ligands (the prototypic myelin-associated inhibitors Nogo, MAG, and OMgp) have originally been identified and characterized as receptor-ligand systems that limit axonal growth and sprouting following spinal cord injury. The physiological role of these proteins in the naive (uninjured) CNS remained largely unknown and is only now beginning to be defined. Our work showed that Nogo receptors function in dendrites. NgR1 regulates dendritic spine morphology and maturation in hippocampal pyramidal CA1 pyramidal neurons. More importantly, we found that the “myelin inhibitors” Nogo and OMgp are present at synapses and regulate activity-dependent synaptic strength. Soluble Nogo and OMgp locally applied to CA3-CA1 synapses suppress long-term potentiation (LTP) in an NgR1 dependent manner. These recent studies significantly broaden our understanding of the functional roles played by “myelin inhibitors” and their receptors and suggest that these molecules serve as key (negative) regulators of structural and functional neuronal plasticity in the mammalian CNS. Because expression of NgR1 itself is regulated by neuronal activity, NgR1 is well suited to link electrical activity to structural changes in mature CNS neurons. We have developed mice mutant for all three NgR family members (NgR1,NgR2,NgR3 triple null mice). These mice are viable into adulthood, allowing us to systematically investigate the role of these proteins in the regulation of dendritic structure and synaptogenesis; activity-dependent synaptic transmission, and hippocampal learning and memory.
Identification of axon derived signals that promote CNS myelination: In vertebrates, including humans, rapid neuronal communication in the peripheral (PNS) and central nervous system (CNS) is dependent on proper myelination. The myelin-forming cell in the PNS is the Schwann cell (SC) and in the CNS the oligodendrocyte (OL). These specialized cells ensheath neuronal processes and thereby facilitate rapid propagation of electrical impulses. While the importance of proper myelination for nervous system function is well recognized, our understanding of the axo-glial communication that directs myelination remains incomplete. Several genes have been identified that, when mutated, cause defects in myelin development or stability of the myelin sheath. One such gene is Fig4/(Sac3), a phosphatidylinositol (3,5)-bisphosphate [PI(3,5)P2] phosphatase. We found that germline ablation of Fig4 leads to an arrest of oligodendrocyte progenitor cell (OPC) maturation, severe hypomyelination, tremor, and juvenile lethality. A remarkable feature of Fig4 deficiency is that neuron-specific expression on a Fig4-/- background is sufficient to rescue the myelination defects. The Fig4 gene encodes an evolutionarily conserved lipid phosphatase that regulates intracellular vesicle trafficking along the endo-lysosomal pathway. Mutation in the human Fig4 gene lead to Charcot Marie Tooth (CMT)4J disease. To understand the molecular mechanisms by which Fig4 deficiency disrupts myelin formation, we employ a mouse genetic approach. Mutant mice with global loss of Fig4 expression (Fig4-/-) exhibit dramatic reduction of myelin in the CNS and PNS, severe tremor, and juvenile lethality. To model human CMT4J, we developed transgenic mice that ubiquitously express low levels of the human disease allele Fig4-I41T on a Fig4-/- background (CMT4J mice). These mice exhibit hypomyelination comparable to that of Fig4-/- mice, but survive to adulthood with many neurologic features of the human disease. We are currently investigating how deficiency of Fig4 in neurons leads to defects in myelination. A more detailed understanding of the molecular mechanism(s) of neuron-directed CNS myelination will have broad significance for biological insight and for clinical applications.
Venkatesh, K., Chivatakarn, O., Lee, H., Joshi, P.S., Kantor, D.B., Newman, B.A., Rose, M., Rader, C., Giger, R.J. (2005) The Nogo-66 Receptor Homologue NgR2 is a Sialic Acid-dependent Receptor Selective for Myelin-Associated Glycoprotein. J. Neurosci. 25, 808-822.
Hofer, T., Tangkeangsirisin, W., Kennedy, M.G., Mage, R.G., Raiker, S.J., Venkatesh, K., Lee, H., Giger, R.J., Rader, C. (2007) Chimeric rabbit/human Fab and IgG specific for members of the Nogo-66 receptor family selected for species cross-reactivity with an improved phage display vector. J. Immunol. Methods, 318(1-2):75-87.
Venkatesh, K., Chivatakarn, O., Sheu, S-S., and Giger, R.J. (2007) Molecular dissection of the myelin-associated glycoprotein receptor complex reveals cell type–specific mechanisms for neurite outgrowth inhibition J. Cell Biology 177(3):393-9.
Chivatakarn, O., Kaneko, S., He, Z., Tessier-Lavigne, M., Giger, R.J. (2007) The Nogo-66 receptor NgR1 is required only for the acute growth-cone collapsing but not the chronic growth inhibitory actions of Myelin Inhibitors. J. Neurosci. 27(27): 7117-24
Lee H., Raiker S.J., Venkatesh, K., Zhang Y., Lee H., Venkatesh K., Shrager P., Yeh, H., and Giger, R.J. (2008) Synaptic Function for the Nogo-66 Receptor NgR1: Regulation of Dendritic Spine Morphology and Activity-Dependent Synaptic Strength. J. Neurosci. 28(11):2753-65
Robak, A.L., Venkatesh K., Lee, H., Raiker, S.J., Duan, Y., Lee-Osbourne, J., Hofer, T., Mage, R.G., Rader, C. and Giger, R.J. (2009) Molecular basis of the interaction of the Nogo-66 Receptor and its homologue NgR2 with Myelin-associated Glycoprotein: Development of NgROMNI-Fc, a novel antagonist of CNS myelin inhibition. J. Neurosci. 29(18):5768-83
Ma, T., Campana, A., Lange, P., Lee, H-H., Banerjee, K., Bryson, B.J., Mahishi, L., Alam, S., Giger, R.J., Barnes S., Morris, S., Willis, D., Twiss, J., Filbin, M.F., and Ratan, R.R. (2010). A large scale chemical screen for regulators of the arginase 1 promoter identifies the soy isoflavone, daidzein as a clinically approved, small molecule that can promote neuronal protection or regeneration via a cAMP-independent pathway. J. of Neurosci. 13;30(2):739-48 (TWIJ article)
Raiker, S.J., Lee, H., Baldwin, K.T., Duan, Y., Shrager, P., and Giger, R.J. (2010) Oligodendrocyte-Myelin Glycoprotein and Nogo negatively regulate activity-dependent synaptic plasticity. J. of Neurosci. 30(37):12432-45
Li, S., Overman, J.J., Katsman, D., Donnelly, C.J., Twiss, J.L., Giger, R.J., Coppola, G., Geschwind, D.H., Carmichael, S.T. (2010) Age-related axonal sprouting transcriptome in cortical neurons after stroke. Nature Neurosci. 13(12):1496-504
Kenneth, M., Bournat, J., Toscano, N., Giger, R.J., Davies, S., (2011) Decorin, erythroblastic leukaemia viral oncogene homologue ErbB4, and signal transducer and activator of transcription SOC3 regulation of semaphorin 3A in central nervous system scar tissue. Brain 134(Pt 4):1140-55
Semavina, M., Saha, N., Kolev, M.V., Goldgur, Y., Giger, R.J., Himanen, J.P., Nikolov, D. (2011). Crystal structure of the Nogo-Receptor-2. Protein Science (4):684-9
Lenk G.M., Ferguson C.J., Chow C.Y., Jin N., Jones J.M., Grant A.E., Zolov S.N., Winters JJ, Giger RJ, Dowling JJ, Weisman LS and Meisler MH (2011) Rescue of neurodegeneration by transgenic expression of a pathogenic variant of FIG4 responsible for Charcot-Marie-Tooth Disease, PLOS Genetics, 7(6):e1002104.
Matsuoka R.L., Chivatakarn O., Badea T.C., Samuels I.S., Cahill H., Katayama K., Kumar S.R., Suto F., Chédotal A., Peachey N.S., Nathans J., Yoshida Y., Giger R.J.*, Kolodkin AL* (2011) Class 5 transmembrane semaphorins control selective mammalian retinal lamination and function. Neuron, 71(3):460-73 *co-corresponding authors
Winters J.J., Ferguson C.J., Lenk G.M., Giger-Mateeva V.I., Shrager P., Meisler M.M., Giger R.J. (2011). Congenital CNS hypomyelination and reduced number of mature oligodendrocytes in mice null for the phosphatidylinositol phosphatase Fig4. J. of Neurosci. 31(48):17736-51. (TWIJ article).
Wills, Z.P., Mandel-Brehm, C., Mardinly, A.R., McCord, A.E., Giger, R.J., Greenberg, M.E. (2012) The Nogo receptor family restricts synapse number in the developing hippocampus. Neuron 73(3): 466-481.
Dickendesher, T.L., Baldwin, K.T., Mironova, Y.A., Koriyama, Y., Raiker, S.J., Askew, K.L., Wood, A., Geoffroy C.G., Zheng, B., Liepmann, C.D., Katagiri, Y., Benowitz, L.I., Geller, H.M., Giger, R.J. (2012) NgR1 and NgR3 are receptors for chondroitin sulfate proteoglycans. Nature Neurosci. 15(5):703-12.
Ferguson, C.J., Lenk, G.M., Jones, J.M., Grant, A.E., Winters, J.J., Dowling, J.J., Giger, R.J., Meisler, H.M. (2012) Neuronal expression of Fig4 is necessary and sufficient to prevent spongiform neurodegeneration. Human Mol. Genetics [Epub ahead of print June 6th]
Stiles, T.L., Dickendesher, T.L., Gaultier, A., Fernandez-Castaneda, A., Mantuano, E., Giger, R.J., and Gonias, S.L. (2012) LDL Receptor-related Protein-1 is a sialic acid-independent receptor for myelin-associated glycoprotein (MAG) and functions in neurite outgrowth inhibition by MAG and CNS myelin. J. Cell Science.
Duan, Y., Wang, S.-H., Song, J., Mironova, Y., Ming, G.L., Kolodkin, A.L., Giger, R.J. (2014) Semaphorin 5A inhibits synaptogenesis in early postnatal- and adult-born hippocampal dentate granule cells. eLife, 2014 Oct 14; 3. doi: 10.7554/eLife.04390.
Baldwin, K.T., Carbajal, K.S., Segal, B.M., and Giger, R.J. (2015) Neuroinflammation triggered by β-glucan/dectin-1 signaling enables CNS axon regeneration. Proc Natl Acad Sci U S A 112(8):2581-6