**8. SOCS proteins and CNS injury**

SOCS2, SOCS3 and SOCS6 all seem to have potential for use as therapeutic targets involving regulation of NPCs following CNS injury. As described earlier, SOCS2 overexpression in‐ creases the survival of newly born neurons in the adult brain under basal, physiological con‐ ditions. It would therefore be very interesting to look at the effects of SOCS2 overexpression under injury conditions in order to determine whether this phenotype would aid in func‐ tional recovery. Similarly, neurogenesis in an SOCS6 overexpressing system under basal and injury conditions should be examined. SOCS3 does not appear to affect neurogenesis *per se* but instead negatively regulates the proliferative and self-renewal effects of LIF on neural precursor cells [193].

SOCS3 has been studied the most extensively under various neural injury conditions, usual‐ ly in concert with effects on neuroinflammation and astrocytes [194-196]. SOCS3 expression is induced or upregulated in various brain regions including hippocampus and lateral ven‐ tricles in response to CNTF administration [197], ischemic stroke [198, 199] and seizure, which also showed transient downregulation of hippocampal SOCS2 expression but no up‐ regulation of SOCS1 [200]. Conversely, after transient forebrain ischemia, SOCS2 expression was upregulated in the hippocampus, not only in astrocytes but also a subset of nestin posi‐ tive NPCs [201].

Expression of SOCS molecules following CNS damage has functional consequences. It was proposed that a major contributor to the poor axonal regeneration after injury was a com‐ promised responsiveness to injury-induced growth factors and cytokines [202]. For example, it was suggested that the transient neuroprotective effect of CNTF on injured neurons was due to CNTF induced negative regulation of cytokine signalling by upregulation of SOCS proteins. Use of a cyclic AMP analogue as an inhibitor of SOCS expression enhanced CNTF induced signalling [203], identifying a new route through which the outcome of neurotrau‐ ma treatments may be improved. Whether such an approach will also regulate and potenti‐ ate effects of cytokines on NPCs remains to be determined. Further, SOCS3 deletion resulted in an enhancement of axonal regeneration in retinal ganglion cells post optic nerve injury in a mouse model, by lifting its inhibitory effects on JAK-STAT signalling [202]. Similarly, PTEN deletion enhanced axon regrowth post injury [204]. PTEN is a negative regulator of signalling via the mammalian target of rapamycin (mTOR) which can be activated through a number of means, one of which being the PI-3K/Akt pathway [205]. Interestingly, much more robust axonal regrowth is achieved upon a simultaneous deletion of PTEN and SOCS3 through a synergistic activation of mTOR and STAT3 signalling pathways [206]. SOCS3 also inhibits the beneficial effects of LIF-mediated oligodendrocyte survival following demyeli‐ nation, with enhanced STAT3 activation and survival of oligodendrocytes from SOCS3 null mice [207].

Thus, it is apparent that there are many aspects to signalling in the processes of adult neuro‐ genesis. The JAK-STAT signalling pathway is one important player, although it is apparent that SOCS proteins can regulate pathways other than JAK/STAT in a cell type dependent manner. The regulation of JAK-STAT signalling by SOCS proteins has enhanced our under‐ standing of the mechanisms of adult neuro- and astrogliogenesis under basal and injury conditions and has opened avenues into the search for potential therapeutic targets for CNS repair.
