Jerry Silver, Ph.D.

Jerry Silver, Ph.D.
Professor
Department of Neurosciences
Case Western Reserve University


School of Medicine E653
10900 Euclid Ave
Cleveland OH, 44106-4975

Phone : (216) 368-2150
Fax : (216) 368-4650
Email : jxs10@case.edu
 
 

RESEARCH INTERESTS

My current research focuses on the role of extrinsic factors in guiding developing and regenerating axons along their proper pathways within the brain and spinal cord of mammals. We are particularly interested in studying the cellular and molecular interactions that occur between axonal growth cones and the various types of glial cells that lie along the presumptive routes and at the boundaries of several different fiber systems in the CNS.

We now know that a variety of cell surface and extracellular matrix molecules that stimulate or inhibit axon growth are made by astroglia during a critical period in development. However, as astroglia mature they change dramatically and alter their interactions with growing axons especially following lesions. Thus, following injury in the adult CNS, so-called reactive astroglia actively block rather than promote sustained axonal elongation. We have concentrated our efforts over the past several years learning whether the boundary molecules that astroglia make during normal development are re-expressed after injury. One of the most interesting families of extracellular matrix molecules, the proteoglycans, were first discovered by my lab to be major players in creating developmental as well as regenerative boundaries. It is our hope that the understanding of normal and abnormal mechanisms of axon guidance will suggest regeneration strategies for altering or overcoming inhibitory molecules that are made in excess. To this end we have developed a microtransplantation technique which enables us to gently inject fully adult neurons into normal or lesioned white matter tracts of the adult CNS, without causing the formation of additional reactive astroglial associated inhibitory molecules via the transplantation itself. Remarkably, the adult nerve cells can regenerate their axons with high efficiency and at high rates of speed challenging long held beliefs that this is impossible. Importantly, the rapidly regenerating axons halt their growth when they reach the glial scar, providing the strongest evidence to date of the major importance of the proteoglycan laden lesion environment in regeneration failure. We have also developed in vitro assays using gradients of proteoglycans that, like the in vivo glial scar, create dystrophic endings on regenerating adult axons. We can now, for the first time, begin to dissect the molecular and cellular machinery of this unusual axonal ending. Many unanswered and provocative questions remain about the potential for neuronal circuit restoration in the regenerated adult CNS and our lab is now in a strong position to begin answering many of them.

Indeed, we have recently been able to promote robust functional regeneration into the adult rodent spinal cord of severed sensory roots using a combinatorial strategy that maximally stimulates an intrinsic growth response in the sensory neurons while simultaneously removing inhibitory proteoglycans from the cord with a bacterial enzyme (ie., chondroitinase) that removes the inhibitory sugar chains from proteoglycans. An even more exciting development is our recent demonstration that combining an autologous peripheral nervous system “bridge” with inhibitory matrix modification via chondroitinase leads to robust, functional regeneration beyond a hemisection lesion of the adult rat spinal cord. This result, in particular, may have far ranging beneficial clinical consequences. Other labs around the world are now showing that the use of chondroitinase combined with various cell bridging techniques and an enhancement of the neurons intrinsic growth response can restore function in other regeneration models and in other species of mammals. It is highly conceivable that such therapeutic strategies may be useful in restoring both sensory and motor function in paralyzed humans.

SELECTED PUBLICATIONS

  1. Grimpe B, Pressman Y, Lupa MD, Horn KP, Bunge MB, Silver J. (2005)
    The role of proteoglycans in Schwann cell/astrocyte interactions and in regeneration failure at PNS/CNS interfaces. Mol Cell Neurosci. 2005 Jan; 28(1):18-29.
  2. Tom VJ, Doller CM, Malouf AT, Silver J. (2004)
    Astrocyte-associated fibronectin is critical for axonal regeneration in adult white matter. J Neurosci. 2004 Oct 20; 24(42):9282-9290.
  3. Tom VJ, Steinmetz MP, Miller JH, Doller CM, Silver J. (2004)
    Studies on the development and behavior of the dystrophic growth cone, the hallmark of regeneration failure, in an in vitro model of the glial scar and after spinal cord injury. J Neurosci. 2004 Jul 21; 24(29):6531-6539.
  4. Grimpe B, Silver J. (2004)
    A novel DNA enzyme reduces glycosaminoglycan chains in the glial scar and allows microtransplanted dorsal root ganglia axons to regenerate beyond lesions in the spinal cord. J Neurosci. 2004 Feb 11; 24(6):1393-1397.
  5. Silver J, Miller JH. (2004)
    Regeneration beyond the glial scar. Nat Rev Neurosci. 2004 Feb; 5(2):146-156.
  6. Butler CD, Schnetz SA, Yu EY, Davis JB, Temple K, Silver J, Malouf AT. (2004)
    Keratan sulfate proteoglycan phosphacan regulates mossy fiber outgrowth and regeneration. J Neurosci. 2004 Jan 14; 24(2):462-473.
  7. Hendricks TJ, Fyodorov DV, Wegman LJ, Lelutiu NB, Pehek EA, Yamamoto B, Silver J, Weeber EJ, Sweatt JD, Deneris ES. (2003)
    Pet-1 ETS gene plays a critical role in 5-HT neuron development and is required for normal anxiety-like and aggressive behavior. Neuron. 2003 Jan 23; 37(2):233-247.
  8. Grimpe B, Silver J. (2002)
    The extracellular matrix in axon regeneration. Prog Brain Res. 2002; 137:333-349.
  9. Grimpe B, Dong S, Doller C, Temple K, Malouf AT, Silver J. (2002)
    The critical role of basement membrane-independent laminin gamma 1 chain during axon regeneration in the CNS. J Neurosci. 2002 Apr 15; 22(8):3144-3160.
  10. Silver J. (2001)
    Robust regeneration in the adult optic system. Exp Neurol. 2001 Dec; 172(2):255-256.
  11. Fitch MT, Doller C, Combs CK, Landreth GE, Silver J. (1999)
    Cellular and molecular mechanisms of glial scarring and progressive cavitation: in vivo and in vitro analysis of inflammation-induced secondary injury after CNS trauma. J Neurosci. 1999 Oct 1; 19(19):8182-8198.
  12. Davies SJ, Goucher DR, Doller C, Silver J. (1999)
    Robust regeneration of adult sensory axons in degenerating white matter of the adult rat spinal cord. J Neurosci. 1999 Jul 15; 19(14):5810-5822.
  13. Xu K, Malouf AT, Messing A, Silver J. (1999)
    Glial fibrillary acidic protein is necessary for mature astrocytes to react to beta-amyloid. Glia. 1999 Feb 15; 25(4):390-403.
  14. DeWitt DA, Perry G, Cohen M, Doller C, Silver J. (1998)
    Astrocytes regulate microglial phagocytosis of senile plaque cores of Alzheimer's disease. Exp Neurol. 1998 Feb; 149(2):329-340.
  15. Fitch MT, Silver J. (1997)
    Activated macrophages and the blood-brain barrier: inflammation after CNS injury leads to increases in putative inhibitory molecules. Exp Neurol. 1997 Dec; 148(2):587-603.
  16. Davies SJ, Fitch MT, Memberg SP, Hall AK, Raisman G, Silver J. (1997)
    Regeneration of adult axons in white matter tracts of the central nervous system. Nature. 1997 Dec 18-25; 390(6661):680-683.
  17. Fitch MT, Silver J. (1997)
    Glial cell extracellular matrix: boundaries for axon growth in development and regeneration. Cell Tissue Res. 1997 Nov; 290(2):379-384.
  18. DeWitt DA, Silver J. (1996)
    Regenerative failure: a potential mechanism for neuritic dystrophy in Alzheimer's disease. Exp Neurol. 1996 Nov; 142(1):103-110.
  19. Canning DR, Hoke A, Malemud CJ, Silver J. (1996)
    A potent inhibitor of neurite outgrowth that predominates in the extracellular matrix of reactive astrocytes. Int J Dev Neurosci. 1996 Jun; 14(3):153-175.
  20. Hoke A, Silver J. (1996)
    Proteoglycans and other repulsive molecules in glial boundaries during development and regeneration of the nervous system. Prog Brain Res. 1996; 108:149-163.
  21. McKeon RJ, Hoke A, Silver J. (1995)
    Injury-induced proteoglycans inhibit the potential for laminin-mediated axon growth on astrocytic scars. Exp Neurol. 1995 Nov; 136(1):32-43.
  22. Brittis PA, Lemmon V, Rutishauser U, Silver J. (1995)
    Unique changes of ganglion cell growth cone behavior following cell adhesion molecule perturbations: a time-lapse study of the living retina. Mol Cell Neurosci. 1995 Oct; 6(5):433-449.
  23. Brittis PA, Silver J. (1995)
    Multiple factors govern intraretinal axon guidance: a time-lapse study. Mol Cell Neurosci. 1995 Oct; 6(5):413-432.
  24. Brittis PA, Meiri K, Dent E, Silver J. (1995)
    The earliest patterns of neuronal differentiation and migration in the mammalian central nervous system. Exp Neurol. 1995 Jul; 134(1):1-12.
  25. Silver J. (1994)
    Inhibitory molecules in development and regeneration. J Neurol. 1994 Dec; 242(1 Suppl 1):S22-S24.
  26. Hoke A, Canning DR, Malemud CJ, Silver J. (1994)
    Regional differences in reactive gliosis induced by substrate-bound beta-amyloid. Exp Neurol. 1994 Nov; 130(1):56-66.
  27. Gonzalez ML, Silver J. (1994)
    Axon-glia interactions regulate ECM patterning in the postnatal rat olfactory bulb. J Neurosci. 1994 Oct; 14(10):6121-6131.
  28. DeWitt DA, Richey PL, Praprotnik D, Silver J, Perry G. (1994)
    Chondroitin sulfate proteoglycans are a common component of neuronal inclusions and astrocytic reaction in neurodegenerative diseases. Brain Res. 1994 Sep 5; 656(1):205-209.
  29. Frisa PS, Goodman MN, Smith GM, Silver J, Jacobberger JW. (1994)
    Immortalization of immature and mature mouse astrocytes with SV40 T antigen. J Neurosci Res. 1994 Sep 1; 39(1):47-56.
  30. Brittis PA, Silver J. (1994)
    Exogenous glycosaminoglycans induce complete inversion of retinal ganglion cell bodies and their axons within the retinal neuroepithelium. Proc Natl Acad Sci U S A. 1994 Aug 2; 91(16):7539-7542.
  31. Herrup K, Silver J. (1994)
    Cortical development and topographic maps: patterns of cell dispersion in developing cerebral cortex. Curr Opin Neurobiol. 1994 Feb; 4(1):108-111.
  32. Hoke A, Silver J. (1994)
    Heterogeneity among astrocytes in reactive gliosis. Perspect Dev Neurobiol. 1994; 2(3):269-274.
  33. Canning DR, McKeon RJ, DeWitt DA, Perry G, Wujek JR, Frederickson RC, Silver J. (1993)
    beta-Amyloid of Alzheimer's disease induces reactive gliosis that inhibits axonal outgrowth. Exp Neurol. 1993 Dec; 124(2):289-298.
  34. Gonzalez Mde L, Malemud CJ, Silver J. (1993)
    Role of astroglial extracellular matrix in the formation of rat olfactory bulb glomeruli. Exp Neurol. 1993 Sep; 123(1):91-105.
  35. Goodman MN, Silver J, Jacobberger JW. (1993)
    Establishment and neurite outgrowth properties of neonatal and adult rat olfactory bulb glial cell lines. Brain Res. 1993 Aug 13; 619(1-2):199-213.
  36. DeWitt DA, Silver J, Canning DR, Perry G. (1993)
    Chondroitin sulfate proteoglycans are associated with the lesions of Alzheimer's disease. Exp Neurol. 1993 Jun; 121(2):149-152.
  37. Pindzola RR, Doller C, Silver J. (1993)
    Putative inhibitory extracellular matrix molecules at the dorsal root entry zone of the spinal cord during development and after root and sciatic nerve lesions. Dev Biol. 1993 Mar; 156(1):34-48.
  38. Silver J, Edwards MA, Levitt P. (1993)
    Immunocytochemical demonstration of early appearing astroglial structures that form boundaries and pathways along axon tracts in the fetal brain. J Comp Neurol. 1993 Feb 15; 328(3):415-436.
  39. Silver J. (1993)
    Glia-neuron interactions at the midline of the developing mammalian brain and spinal cord. Perspect Dev Neurobiol. 1993; 1(4):227-236.
  40. Brittis PA, Canning DR, Silver J. (1992)
    Chondroitin sulfate as a regulator of neuronal patterning in the retina. Science. 1992 Feb 7; 255(5045):733-736.
  41. McKeon RJ, Schreiber RC, Rudge JS, Silver J. (1991)
    Reduction of neurite outgrowth in a model of glial scarring following CNS injury is correlated with the expression of inhibitory molecules on reactive astrocytes. J Neurosci. 1991 Nov; 11(11):3398-3411.
  42. Lefkowitz M, Durand D, Smith G, Silver J. (1991)
    Electrical properties of axons within probst bundles of acallosal mice and callosi that have reformed upon glial-coated polymer implants. Exp Neurol. 1991 Sep; 113(3):306-313.
  43. Watanabe M, Rutishauser U, Silver J. (1991)
    Formation of the retinal ganglion cell and optic fiber layers. J Neurobiol. 1991 Jan; 22(1):85-96.
  44. Rudge JS, Silver J. (1990)
    Inhibition of neurite outgrowth on astroglial scars in vitro. J Neurosci. 1990 Nov; 10(11):3594-3603.
  45. Schneider BF, Silver J. (1990)
    Failure of the subcallosal sling to develop after embryonic X-irradiation is correlated with absence of the cavum septi. J Comp Neurol. 1990 Sep 22; 299(4):462-469.
  46. Snow DM, Lemmon V, Carrino DA, Caplan AI, Silver J. (1990)
    Sulfated proteoglycans in astroglial barriers inhibit neurite outgrowth in vitro. Exp Neurol. 1990 Jul; 109(1):111-130.
  47. Siegal JD, Kliot M, Smith GM, Silver J. (1990)
    A comparison of the regeneration potential of dorsal root fibers into gray or white matter of the adult rat spinal cord. Exp Neurol. 1990 Jul; 109(1):90-97.
  48. Kliot M, Smith GM, Siegal JD, Silver J. (1990)
    Astrocyte-polymer implants promote regeneration of dorsal root fibers into the adult mammalian spinal cord. Exp Neurol. 1990 Jul; 109(1):57-69.
  49. Smith GM, Rutishauser U, Silver J, Miller RH. (1990)
    Maturation of astrocytes in vitro alters the extent and molecular basis of neurite outgrowth. Dev Biol. 1990 Apr; 138(2):377-390.
  50. Snow DM, Steindler DA, Silver J. (1990)
    Molecular and cellular characterization of the glial roof plate of the spinal cord and optic tectum: a possible role for a proteoglycan in the development of an axon barrier. Dev Biol. 1990 Apr; 138(2):359-376.
  51. Rudge JS, Smith GM, Silver J. (1989)
    An in vitro model of wound healing in the CNS: analysis of cell reaction and interaction at different ages. Exp Neurol. 1989 Jan; 103(1):1-16.
  52. Hankin MH, Silver J. (1988)
    Development of intersecting CNS fiber tracts: the corpus callosum and its perforating fiber pathway. J Comp Neurol. 1988 Jun 8; 272(2):177-190.
  53. Hankin MH, Schneider BF, Silver J. (1988)
    Death of the subcallosal glial sling is correlated with formation of the cavum septi pellucidi. J Comp Neurol. 1988 Jun 8; 272(2):191-202.
  54. Webster MJ, Shatz CJ, Kliot M, Silver J. (1988)
    Abnormal pigmentation and unusual morphogenesis of the optic stalk may be correlated with retinal axon misguidance in embryonic Siamese cats. J Comp Neurol. 1988 Mar 22; 269(4):592-611.
  55. Holley JA, Silver J. (1987)
    Growth pattern of pioneering chick spinal cord axons. Dev Biol. 1987 Oct; 123(2):375-388.
 
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