Nogo-66 Receptor Prevents Raphespinal and Rubrospinal Axon Regeneration and Limits Functional Recovery from Spinal Cord Injury

Abstract

Axon regeneration after injury to the adult mammalian CNS is limited in part by three inhibitory proteins in CNS myelin: Nogo-A, MAG, and OMgp. All three of these proteins bind to a Nogo-66 receptor (NgR) to inhibit axonal outgrowth in vitro. To explore the necessity of NgR for responses to myelin inhibitors and for restriction of axonal growth in the adult CNS, we generated ngr(-/-) mice. Mice lacking NgR are viable but display hypoactivity and motor impairment. DRG neurons lacking NgR do not bind Nogo-66, and their growth cones are not collapsed by Nogo-66. Recovery of motor function after dorsal hemisection or complete transection of the spinal cord is improved in the ngr(-/-) mice. While corticospinal fibers do not regenerate in mice lacking NgR, regeneration of some raphespinal and rubrospinal fibers does occur. Thus, NgR is partially responsible for limiting the regeneration of certain fiber systems in the adult CNS.

Selective temporal and regional alterations of Nogo-A and small proline-rich repeat protein 1A (SPRR1A) but not Nogo-66 receptor (NgR) occur following traumatic brain injury in the rat

“…As an example, NgR mRNA and protein are unevenly distributed in the adult CNS with some important regions lacking NgR (see Hunt et al, 2002a,b) and mechanisms other than Nogo/NgR interactions must explain the lack of axonal regeneration in these areas. In addition, using mice deficient in Nogo-A or NgR, some reports have shown axonal regeneration and marked behavioral improvement following SCI Kim et al, 2003Kim et al, , 2004, whereas other studies did not detect any differences when compared to their wild-type littermates (Zheng et al, 2003(Zheng et al, , 2005. Other recent reports have suggested a more complex role for Nogo other than associated with inhibition of axonal outgrowth (Jokic et al, 2005;He et al, 2004;Karnezis et al, 2004;Acevado et al, 2004).…”

White matter inhibitors in CNS axon regeneration failure

“…Both groups failed to observe enhanced axon regeneration in the CST of NgR1 mutants, an unexpected finding given that NgR1 can mediate the inhibitory effect of all three prototypical myelin inhibitors (Kim et al, 2004;Zheng et al, 2005). Interestingly, one group found enhanced regeneration of the raphespinal and rubrospinal fiber tracts and improved motor function after complete transection (Kim et al, 2004). The selective enhancement of regeneration in certain axonal tracts in this NgR1 mutant may reflect differences in the intrinsic regenerative capacity of various axonal populations or a differential response of axonal tracts to NgR1 deletion.…”

“…Two groups independently generated and characterized NgR1 null mice. Both groups failed to observe enhanced axon regeneration in the CST of NgR1 mutants, an unexpected finding given that NgR1 can mediate the inhibitory effect of all three prototypical myelin inhibitors (Kim et al, 2004;Zheng et al, 2005). Interestingly, one group found enhanced regeneration of the raphespinal and rubrospinal fiber tracts and improved motor function after complete transection (Kim et al, 2004).…”

“…In a growth cone collapse assay, NgR1-deficient postnatal dorsal root ganglion neurons are less sensitive than wild type neurons to solubilized myelin inhibitors (Kim et al, 2004). However, in a neurite outgrowth assay, NgR1 deficient postnatal cerebellar postnatal granule neurons or dorsal root ganglion neurons are as inhibited as wild type neurons by immobilized myelin or Nogo-66 substrate (Zheng et al, 2005).…”

Corticotrophin-releasing hormone (CRH) facilitates axon outgrowth

“…The fact is supported by using an antibody against the Nogo-66 receptor, or knockdown of the Nogo-66 receptor gene that can conceptually attenuate the inhibitory effect on new axon growth, although not completely. 4,5 However, the regulatory mechanism is to be further understood.…”