Zhigang He is interested in why lesioned axons cannot regenerate in the adult mammalian central nervous system (CNS). His research has been focused on two potential mechanisms: the inhibitory activity in the adult lesion sites and reduced intrinsic ability associated with mature CNS neurons.
Previous studies indicate that the inhibitory activity is principally associated with components of CNS myelin and molecules in the glial scar at the lesion site. Recent studies from He's laboratory and others suggested that three myelin proteins -- myelin-associated glycoprotein (MAG), Nogo-A and oligodendrocyte myelin glycoprotein (OMgp) -- collectively account for the majority of the inhibitory activity in CNS myelin. The inhibitory activity of MAG, OMgp and the extracellular domain of Nogo-A might be mediated by a receptor complex with a Nogo receptor and at least two co-receptors, p75/TROY and Lingo-1. Blocking such inhibitory activity by genetic and pharmacological approaches could promote local axonal sprouting and reactivate structural plasticity but is not sufficient to allow long-distance axon regeneration.
Our current studies are aimed to define cellular and molecular mechanisms underlying the intrinsic regenerative capacity of mature neurons. He and his colleagues envision two main possibilities for the lack of axon re-growth responses after an injury: (1) the signals carrying information of axotomy fail to reach to the cell body for activating regenerative program; and/or (2) the axonal growth program could not to be reactivated even if the retrograde signals are delivered to the cell bodies. They are addressing these issues by a combination of in vitro and in vivo approaches.