**7. Roles of other SOCS proteins in the CNS**

Other SOCS proteins also have roles in the modulation of signalling in the adult CNS. Other than SOCS2, SOCS3 is the best functionally characterised SOCS protein thus far. SOCS3 plays a role in the regulation of neural stem cell fate. Its overexpression in neural stem cells has been shown to inhibit astrogliogenesis and promote neurogenesis through the inhibition of STAT3 transcriptional activity [156]. More recently, SOCS6 involvement in neuronal dif‐ ferentiation was also established. Exogenous IGF1 was found to enhance neurite outgrowth and dendritic branching of neural stem cells through the induction of SOCS6 expression. The same phenotype was produced independently of IGF-1 by SOCS6 overexpression alone. Similar to SOCS2, SOCS6 is activated through the JAK2/STAT5 pathway, however, in this case it is activated through signalling via the IGF receptor. Activated STAT5 induces SOCS6 expression, which goes on to inhibit STAT5 mediated signalling following the classic nega‐ tive feedback loop [191]. SOCS7 also plays a major role in the brain with SOCS7 null mice exhibiting severe hydrocephalus in early adulthood [192]. While the mechanism by which this occurs has not been elucidated, given the close relationship of ependymal cells and the ventricular space to NPCs in the SVZ, it is tempting to speculate that SOCS7 may also regu‐ late adult NPC biology.

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

Regulation of Basal and Injury-Induced Fate Decisions of Adult Neural Precursor Cells: Focus on SOCS2 and Related

Signalling Pathways

253

http://dx.doi.org/10.5772/53268

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

We acknowledge support from Stem Cells Australia and A.M.T. is supported by an

Centre for Neuroscience Research, Department of Anatomy and Neuroscience, The Univer‐

mice [207].

repair.

**Acknowledgments**

**Author details**

NH&MRC Research Fellowship (#628344).

sity of Melbourne, Victoria, Australia

Harleen S. Basrai, Kimberly J. Christie and Ann M. Turnley\*

\*Address all correspondence to: turnley@unimelb.edu.au
