Cell and Developmental Biology University of Michigan

Research

Nervous System Regeneration: Molecular Mechanisms that Limit Axonal Regeneration Following Spinal Cord Injury, Optic Nerve Injury and Multiple Sclerosis.

An adult mouse hippocampus, with the mature cells of the dentate gyrus labeled with calbindin (green), the immature cells labeled with calretinin (red), and the nuclei labeled with Hoechst stain (blue).

Dorsal root ganglion (DRG) neurons in culture, dissected and dissociated from a postnatal day 7 (P7) mouse and stained with betaIII-tubulin (green) to label the processes.

A mouse optic nerve stained with GAP-43 (green) to label regenerating retinal ganglion cell (RGC) axons following an injury. Wildtype mouse RGCs do not regenerate past the lesion site (asterisk); however, these RGCs lack the Nogo receptors NgR1, NgR2, and NgR3, and are further stimulated to grow with injection of the yeast cell wall extract Zymosan.

Diseases/Research Topics

Nervous System Regeneration, Spinal Cord Injury, Optic Nerve Injury, Multiple Sclerosis, Axon Stability, Wallerian Degeneration, Axon Regeneration, Axon Growth, Axon Guidance, Synaptic Plasticity, Mouse Genetics.

A long standing goal of our research is to understand how neuronal growth and sprouting is regulated in the mammalian nervous system during development, adult neuronal plasticity, and following injury(i.e. spinal cord injury, traumatic brain injury, stroke or multiple sclerosis). 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), and myelin-associated inhibitors/chondroitin sulfate proteoglycans and their receptors.

The Nogo receptors NgR1 and NgR2, as well as paired immunoglobulin-like receptor B (PirB), have been implicated in regulating acute neuronal responses to the myelin inhibitors Nogo/RTN4, myelin-associated glycoprotein (MAG), and oligodendrocyte-myelin glycoprotein (OMgp). We are currently investigating the importance of these high-affinity receptors in mediating cell-type specific inhibition in vitro and in vivo, as well as the signaling pathways that are subsequently activated. We have also identified a novel function for NgR1 in regulating activity-dependent synaptic strength. Ongoing studies are aimed at understanding the mechanisms of how enhanced neuronal plasticity leads to improved functional outcomes following nervous system injury.

In addition, we recently identified the Nogo receptors NgR1 and NgR3 as novel receptors for a second major group of growth inhibitors, the chondroitin sulfate proteoglycans (CSPGs). Thus, myelin inhibitors and CSPGs employ overlapping yet distinct members of the Nogo receptor family to signal neuronal growth inhibition. We are currently investigating the significance of this interaction in vitro and in vivo.

A third line of investigation is focused on mechanisms of axon-glia interaction during nervous system development, adult homeostasis and disease. Myelin-associated glycoprotein (MAG) has an axon protective function in vivo; however, the mechanisms of MAG-mediated axon protection are poorly understood. We have identified the Nogo receptor family member NgR2 as a high-affinity receptor for MAG and we are currently investigating the role of NgR2 in MAG signaling in vivo.

Reactive astrocytes (red) in culture, which are producing inhibitory
chondroitin sulfate proteoglycans (green).

An embryonic rat dorsal root ganglion (DRG) explant (green), which is strongly repelled by COS-7 cells (red) expressing a TdTomato-Semaphorin3A fusion protein.

Mouse hippocampal neurons forming presynaptic terminals (red) onto COS-7 cells co-expressing GFP and the presynaptic organizer neuroligin 3 (green).

Giger Lab 2011!

Lab Members

• Yuntao Duan
  Research Investigator
• Katherine Baldwin
  Graduate Student
• Travis Lee Dickendesher
  Graduate Student
• Yevgeniya Mironova
  Graduate Student
• Derek Fedeson
  Undergraduate Student
• Sandy Ng
  Undergraduate Student
• Dava Batjargal
  Undergraduate Student
• Sophia Sung Eun Park
  Undergraduate Student

Publications

Representative Publications

• Dickendesher TL, Baldwin KT, Mironova YA, Koriyama Y, Raiker SJ, Askew KL, Wood A, Geoffroy CG, Zheng B, Liepmann CD, Katagiri Y, Benowitz LI, Geller HM, Giger RJ (2012) NgR1 and NgR3 are receptors for chondroitin sulfate proteoglycans. Nat Neurosci 15(5):703-12.
• Wills ZP, Mandel-Brehm C, Mardinly AR, McCord AE, Giger RJ, Greenberg ME (2012) The nogo receptor family restricts synapse number in the developing hippocampus. Neuron 73(3):466-81.
• Winters JJ, Ferguson CJ, Lenk GM, Giger-Mateeva VI, Shrager P, Meisler MH, Giger RJ (2011) Congenital CNS hypomyelination in the Fig4 null mouse is rescued by neuronal expression of the PI(3,5)P(2) phosphatase Fig4. J Neurosci 31(48):17736-51.
• Matsuoka RL, Chivatakarn O, Badea TC, Samuels IS, Cahill H, Katayama K, Kumar SR, Suto F, Chédotal A, Peachey NS, Nathans J, Yoshida Y, Giger RJ, Kolodkin AL (2011) Class 5 transmembrane semaphorins control selective Mammalian retinal lamination and function. Neuron 71(3):460-73.
• Dickendesher TL, Giger RJ (2011) VEGF shows its attractive side at the midline. Neuron 70(5):808-12.
• Raiker SJ, Lee H, Baldwin KT, Duan Y, Shrager P, Giger RJ (2010) Oligodendrocyte-myelin glycoprotein and Nogo negatively regulate activity-dependent synaptic plasticity. J Neurosci 30(37):12432-45.
• Giger RJ, Hollis ER 2nd, Tuszynski MH (2010) Guidance molecules in axon regeneration. Cold Spring Harb Perspect Biol 2(7):a001867.
• Duan Y, Giger RJ (2010) A new role for RPTPsigma in spinal cord injury: signaling chondroitin sulfate proteoglycan inhibition. Sci Signal 23;3(110):pe6.
• Pasterkamp RJ, Giger RJ (2009) Semaphorin function in neural plasticity and disease. Curr Opin Neurobiol 19(3):263-74.
• Robak LA, Venkatesh K, Lee H, Raiker SJ, Duan Y, Lee-Osbourne J, Hofer T, Mage RG, Rader C, Giger RJ (2009) Molecular basis of the interactions of the Nogo-66 receptor and its homolog NgR2 with myelin-associated glycoprotein: development of NgROMNI-Fc, a novel antagonist of CNS myelin inhibition. J Neurosci 29(18):5768-83.
• Giger RJ, Venkatesh K, Chivatakarn O, Raiker SJ, Robak L, Hofer T, Lee H, Rader C (2008) Mechanisms of CNS myelin inhibition: evidence for distinct and neuronal cell type specific receptor systems. Restor Neurol Neurosci 26(2-3):97-115.
• Lee H, Raiker SJ, Venkatesh K, Geary R, Robak LA, Zhang Y, Yeh HH, Shrager P, Giger RJ (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.
• Chivatakarn O, Kaneko S, He Z, Tessier-Lavigne M, Giger RJ (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.
• Venkatesh K, Chivatakarn O, Sheu SS, Giger RJ (2007) Molecular dissection of the myelin-associated glycoprotein receptor complex reveals cell type-specific mechanisms for neurite outgrowth inhibition. J Cell Biol 177(3):393-9.
• Kornack DR, Giger RJ (2005) Probing microtubule +TIPs: regulation of axon branching. Curr Opin Neurobiol 15(1):58-66.
• Venkatesh K, Chivatakarn O, Lee H, Joshi PS, Kantor DB, Newman BA, Mage R, Rader C, Giger RJ (2005) The Nogo-66 receptor homolog NgR2 is a sialic acid-dependent receptor selective for myelin-associated glycoprotein. J Neurosci 25(4):808-22.
• Kantor DB, Chivatakarn O, Peer KL, Oster SF, Inatani M, Hansen MJ, Flanagan JG, Yamaguchi Y, Sretavan DW, Giger RJ, Kolodkin AL (2004) Semaphorin 5A is a bifunctional axon guidance cue regulated by heparan and chondroitin sulfate proteoglycans. Neuron 44(6):961-75.