Conversely, its downregulation by shRNA dramatically enhanced the polarity of migrating neurons by increasingthelengthofleadingandtrailingprocesses. Thisroleof KLF4 would seem to oppose the perform of a number of genes that advertise neuronal migration, this kind of as neurogenin 2, CDK5, and semaphorin 3A. It will be exciting to examine whetherKLF4geneticallyinteractswiththesefactorsinthefuture. Seeing that cytoskeletal dynamics play a vital function in neurite out growthandduringradialneuronalmigration,KLF4maytran scriptionally regulate the expression of genes involved with the for mation of your cytoskeleton in establishing neurons. Supporting this hypothesis could be the nding that KLF4 right controls keratins, a loved ones of intermediate laments connected with cellular vary entiation and cytoskeletal organization. It should be mentioned, on the other hand, that knockdown of KLF4 in vivo has no long run result over the nal place or morphology of mature neurons.
This re sult indicates that establishing neurons, also as regenerating neurons following injury or in culture, are additional sensitive than mature neurons to your lowered expression degree of KLF4. KLF4 expression is directly activated by JAK STAT3 signaling inresponsetoLIFtreatmentinESCs. Thispathwayisimpor tant for the two ESC self renewal and servicing of pluripotency. Similarly, our existing examine showed that KLF4 is inducedinculturedNSCsbyLIF. Interestingly,wealsofoundthat overexpression selelck kinase inhibitor of KLF4 can further improve activation of STAT3 by rising its phosphorylation at Y705. However, as opposed to selling self renewal of NSCs, overexpression of KLF4 inhibits their proliferation and induces the expression of GFAP. At a later stage, cells with constitutive expression of KLF4 express markers ofglialcells,suchasGS,GFAP,andNG2. Theseobservationsmay not be sudden since activation of JAK STAT3 signaling in NSCs has become previously proven to advertise gliogenesis. While in early neural growth, gliogenesis is suppressed by neurogenic aspects such as neurogenin 1 and 2.
Along with marketing neuronal differentiation, neurogenins also repress glial differentiation by inhibiting JAK STAT3 signaling. This kind of inhibition is completed both by BIBF1120

lowering STAT3 phosphorylation and by sequestering the CBP/ p300 Smad1 complicated far from STAT3. By enhancing acti vation of STAT3, KLF4 may possibly oppose the neurogenic functions of neurogenins. Moreover, KLF4 was shown to immediately bind to co issue CBP/p300, therefore reducing its availability to neuro genins and further tipping the balance toward gliogenesis. Inter estingly, emerging evidence also back links neurogenesis to molecular machinery that controls migration.