Retinoic acid (RA) promotes axon regeneration by silencing a key inhibitory receptor, Puttagunta et al. report.
Neuronal regrowth after injury is limited, in part, by inhibitory proteins released upon disruption of the surrounding myelin sheath. These proteins bind to the Nogo receptor complex on the neuronal plasma membrane, thereby activating the RhoA GTPase to initiate growth cone collapse. On the other hand, neuron regeneration can be boosted by the RA receptor RAR-β, although the mechanisms by which this transcription factor promotes axon growth remain unclear.
Puttagunta et al. found that RA and RAR-β specifically counteract the inhibitory Nogo receptor pathway. RA promoted the outgrowth of neurites from wild-type neurons in the presence of inhibitory myelin proteins but had no effect on neurons lacking RAR-β. In the presence of RA, RAR-β down-regulated a key component of the Nogo receptor complex called Lingo-1 by binding to Lingo-1's promoter and repressing its transcription. RA no longer reversed myelin-dependent inhibition of axonal growth if Lingo-1 was overexpressed in cultured neurons.
The researchers also found that treating mice with RA following a spinal cord injury repressed Lingo-1 expression, whereas Lingo-1 levels remained high in mice lacking RAR-β. Senior author Simone Di Giovanni now wants to investigate whether boosting RAR-β activity at the right time after injury can improve neuron recovery and whether the RA signaling pathway promotes neurite outgrowth by other mechanisms in addition to inhibition of the Nogo receptor complex.