The failure of axonal regeneration in mammalian central nervous system is attributed to hostile environment from myelin and the diminished instrinsic regenerative capacity of mature neurons. Axotomy of the peripheral branches of dorsal root ganglion neurons results in robust regeneration such that they can regenerate their central branches in lesioned spinal dorsal column. The roles of three transcription factors ATF3, Stat3 and Smad1 will be studied by using RNA interference for acute gene-silencing and Sindbis virus for overexpression. To dissect the molecular pathways involved in mediating myelin inhibition, the possibly redundant roles of p75 and TROY, NgR1 and its homologues NgR2 and NgR3 will be investigated by conducting myelin inhibition assays on dissociated neurons and explants of both dorsal root ganglion and cerebellar granule cells from wild-type, p75-/-, TROY-/-, NgR-/- mice or double mutant mice. RNA interference will be used for multiple knockdown. Epistasis analysis will be conducted to study the pathway relationships between the p75/NgR receptor complex and epidermal growth factor receptor (EGFR). Such understanding can help elucidate mechanisms of both intrinsic growth state and extrinsic myelin inhibition. ? ?
| Zou, Hongyan; Ho, Carole; Wong, Karen et al. (2009) Axotomy-induced Smad1 activation promotes axonal growth in adult sensory neurons. J Neurosci 29:7116-23 |
