Embryonic Neurons Adapt to the Inhibitory Proteoglycan Aggrecan by Increasing Integrin Expression

Condic, Maureen L.; Snow, Diane; Letourneau, Paul C.

doi:10.1523/jneurosci.19-22-10036.1999

Cited by 116 publications

(107 citation statements)

References 51 publications

Supporting

Mentioning

100

Contrasting

Unclassified

Order By: Relevance

“…Whether NT-3 has a similar effect is unknown. Alternately, NT-3-treated neurons might upregulate receptors for growth- (Rosario et al, 1992;Kozlova et al, 1994;Golding et al, 1996Golding et al, , 1999, possibly the result of increased laminin-binding integrin expression by the embryonic neurons (Condic et al, 1999). NGF increases the expression of integrins in PC-12 cells and causes their accumulation in sympathetic growth cones (Rossino et al, 1990;Zhang et al, 1993;Grabham and Goldberg, 1997).…”

Section: Nt-3-mediated Bypassing Of Barrier Onementioning

confidence: 99%

Two-Tiered Inhibition of Axon Regeneration at the Dorsal Root Entry Zone

Ramer

Duraisingam²,

Priestley

et al. 2001

J. Neurosci.

View full text Add to dashboard Cite

Glial-derived inhibitory molecules and a weak cell-body response prevent sensory axon regeneration into the spinal cord after dorsal root injury. Neurotrophic factors, particularly neurotrophin-3 (NT-3), may increase the regenerative capacity of sensory neurons after dorsal rhizotomy, allowing regeneration across the dorsal root entry zone (DREZ). Intrathecal NT-3, delivered at the time of injury, promoted an upregulation of the growth-associated protein GAP-43 primarily in large-diameter sensory profiles (which did not occur after rhizotomy alone), as well as regeneration of cholera toxin B-labeled sensory axons across the DREZ and deep into the dorsal horn. However, delaying treatment for 1 week compromised regeneration: although axons still penetrated the DREZ, growth within white matter was qualitatively and quantitatively restricted. This was not associated with an impaired cell-body response (GAP-43 upregulation was equivalent for both immediate and delayed treatments), or with astrogliosis at the DREZ, which begins almost immediately after rhizotomy, but with the delayed appearance of mature ED1-expressing phagocytes in the dorsal white matter between 1 and 2 weeks after lesion, marking the beginning of myelin breakdown. After rhizotomy with immediate NT-3 treatment, regeneration continues beyond 2 weeks, but in the dorsal gray matter rather than in the degenerating dorsal columns. The ability of NT-3 to promote regeneration across the DREZ, but not after the beginning of degeneration after delayed treatment reveals a hierarchy of inhibitory influences: the astrogliotic, but not the degenerative barrier is surmountable by NT-3 treatment. Key words: neurotrophin-3; regeneration; degeneration; astrocytes; oligodendrocytes; myelin; dorsal root ganglionThe differential abilities of peripheral and central nervous tissue to support regeneration is exemplified at the dorsal root entry zone (DREZ), which marks the entry point of primary afferent axons into the spinal cord. Here, the environment changes abruptly from consisting of growth-permissive Schwann cells, to astrocytes, oligodendrocytes, and microglia, which may all inhibit regeneration (Fawcett and Asher, 1999). On contact with the DREZ, regenerating axons form club-like end bulbs or synapselike structures, (Ramon y Cajal, 1928;Carlstedt, 1985), but because of the prohibitive environment of the CNS and a paltry regenerative response of sensory neurons to rhizotomy, they never re-enter the adult cord.One strategy to encourage regeneration is to enhance the growth response of the rhizotomized neurons. GAP-43 is induced in nearly all neurons during peripheral nerve regeneration (Verge et al., 1990b), but in few neurons after rhizotomy (Schreyer and Skene, 1993), unless the root is severed very close to the DRG (Chong et al., 1996). Dorsal root axonal growth occurs at about half the rate of peripheral axons (Wujek and Lasek, 1983;Oblinger and Lasek, 1984). An experimental "conditioning" lesion to a peripheral nerve before dorsal rhizotomy doubles the rate of ...

show abstract

Section: Nt-3-mediated Bypassing Of Barrier Onementioning

confidence: 99%

Two-Tiered Inhibition of Axon Regeneration at the Dorsal Root Entry Zone

Ramer

Duraisingam²,

Priestley

et al. 2001

J. Neurosci.

View full text Add to dashboard Cite

show abstract

“…Chief of the many ECM molecules that serve to inhibit axonal regeneration are the chondroitin sulfate proteoglycans (CSPGs) (Eddleston and Mucke, 1993;Silver and Miller, 2004) that experience a great increase in expression following SCI (Lemons et al, 1999;McKeon et al, 1991). Both in vitro and in vivo studies have shown that axons do not extend into CSPG-rich ECM (Davies et al, 1997(Davies et al, , 1999McKeon et al, 1991;Meiners et al, 1995;Zuo et al, 1998), and specific CSPGs that inhibit neurite outgrowth have been identified including: aggrecan (Condic et al, 1999), neurocan , phosphocan , brevican (Yamada et al, 1997), versican (Schmalfeldt et al, 2000), and NG2 (Dou and Levine, 1994).…”

Section: Introductionmentioning

confidence: 99%

Conditional Sox9 ablation reduces chondroitin sulfate proteoglycan levels and improves motor function following spinal cord injury

McKillop

Dragan

Schedl

et al. 2012

Glia

View full text Add to dashboard Cite

Chondroitin sulfate proteoglycans (CSPGs) found in perineuronal nets and in the glial scar after spinal cord injury have been shown to inhibit axonal growth and plasticity. Since we have previously identified SOX9 as a transcription factor that upregulates the expression of a battery of genes associated with glial scar formation in primary astrocyte cultures, we predicted that conditional Sox9 ablation would result in reduced CSPG expression after spinal cord injury and that this would lead to increased neuroplasticity and improved locomotor recovery. Control and Sox9 conditional knock-out mice were subject to a 70 kdyne contusion spinal cord injury at thoracic level 9. One week after injury, Sox9 conditional knock-out mice expressed reduced levels of CSPG biosynthetic enzymes (Xt-1 and C4st), CSPG core proteins (brevican, neurocan, and aggrecan), collagens 2a1 and 4a1, and Gfap, a marker of astrocyte activation, in the injured spinal cord compared with controls. These changes in gene expression were accompanied by improved hind limb function and locomotor recovery as evaluated by the Basso Mouse Scale (BMS) and rodent activity boxes. Histological assessments confirmed reduced CSPG deposition and collagenous scarring at the lesion of Sox9 conditional knock-out mice, and demonstrated increased neurofilament-positive fibers in the lesion penumbra and increased serotonin immunoreactivity caudal to the site of injury. These results suggest that SOX9 inhibition is a potential strategy for the treatment of SCI.

show abstract

“…After development, some integrin receptors are downregulated, resulting in adult neurons that are unable to interact with certain matrix molecules, including TN-C (Jones, 1996;Pinkstaff et al, 1999), and cells may lose the ability to regulate surface integrin levels to optimize cell-matrix interactions. For example, embryonic neurons adapt to allow growth on inhibitory substrates such as aggrecan by increasing expression of distinct integrins (Condic et al, 1999), whereas adult neurons are unable to respond similarly (Condic, 2001). To obtain optimal regeneration from dorsal root ganglion (DRG) neurons on laminin and fibronectin, it was necessary to overexpress ␣1 and ␣5 integrin subunits, which combine with the pool of ␤1 subunit to produce receptors for laminin and fibronectin, promoting axon growth (Condic 2001).…”

Section: Introductionmentioning

confidence: 99%

α9 Integrin Promotes Neurite Outgrowth on Tenascin-C and Enhances Sensory Axon Regeneration

Andrews¹,

Czvitkovich²,

Dassie³

et al. 2009

J. Neurosci.

146

162

View full text Add to dashboard Cite

Damaged CNS axons are prevented from regenerating by an environment containing many inhibitory factors. They also lack an integrin that interacts with tenascin-C, the main extracellular matrix glycoprotein of the CNS, which is upregulated after injury. The ␣9␤1 integrin heterodimer is a receptor for the nonalternatively spliced region of tenascin-C, but the ␣9 subunit is absent in adult neurons. In this study, we show that PC12 cells and adult rat dorsal root ganglion (DRG) neurons do not extend neurites on tenascin-C. However, after forced expression of ␣9 integrin, extensive neurite outgrowth from PC12 cells and adult rat DRG neurons occurs. Moreover, both DRG neurons and PC12 cells secrete tenascin-C, enabling ␣9-transfected cells to grow axons on tissue culture plastic. Using adeno-associated viruses to express ␣9 integrin in vivo in DRGs, we examined axonal regeneration after cervical dorsal rhizotomy or dorsal column crush in the adult rat. After rhizotomy, significantly more dorsal root axons regrew into the dorsal root entry zone at 6 weeks after injury in ␣9 integrinexpressing animals than in green fluorescent protein (GFP) controls. Similarly, after a dorsal column crush injury, there was significantly more axonal growth into the lesion site compared with GFP controls at 6 weeks after injury. Behavioral analysis after spinal cord injury revealed that both experimental and control groups had an increased withdrawal latency in response to mechanical stimulation when compared with sham controls; however, in response to heat stimulation, normal withdrawal latencies returned after ␣9 integrin treatment but remained elevated in control groups.

show abstract

Embryonic Neurons Adapt to the Inhibitory Proteoglycan Aggrecan by Increasing Integrin Expression

Cited by 116 publications

References 51 publications

Two-Tiered Inhibition of Axon Regeneration at the Dorsal Root Entry Zone

Two-Tiered Inhibition of Axon Regeneration at the Dorsal Root Entry Zone

Conditional Sox9 ablation reduces chondroitin sulfate proteoglycan levels and improves motor function following spinal cord injury

α9 Integrin Promotes Neurite Outgrowth on Tenascin-C and Enhances Sensory Axon Regeneration

Contact Info

Product

Resources

About