On the other hand, baseline ERK1 2 activity and LPS induced JNK1 2 activation w

SVZ lysates from the mice that were injected systemically over a three day period showed that the proliferative marker Ki67 was upregulated 30% by each of the FAK inhibitors. Expression of epi dermal growth factor receptor, a marker for tran purchase 17-AAG sient amplifying progenitor SVZ cells, was similarly increased. In another set of mice, FAK inhibi tor PF573228 caused a 56% increase in the number of SVZ neuroblasts stained for their marker doublecortin, confirming that neurogenesis was induced. The SVZ clearly was thicker after systemic FAK inhibitor treatment, representing more DCX cells as shown in confocal images. Discussion Astrocytes express a number of integrins which are well known for roles in cell morphology and adhesion, including vB5 integrin.<br><br> This study identifies an vB5 integrin signaling pathway that regulates gene transcription, inhibiting glial CNTF expression. We can not rule out that other integrins also repress CNTF supplier 17-DMAG as we did not block all integrin subunits, specifically vB8. How ever, astrocytes respond differently to vitronectin via vB5 and vB8 integrin, suggesting that they activate differ ent signaling pathways. Also, adult astrocytes lack vB8 integrin. Our data show selectivity of integrins in regulating CNTF, where blockade of v and B5, but not 6 or B1 subunits induced CNTF expression in astroglioma cells. Cell cell contact enables cultured astrocytes to sup port oligodendrocyte survival through the 6B1, but not other integrins. Thus, individual integrins have spe cific roles for regulating gene expression.<br><br> CNTF is a member of a cytokine family, including pro inflammatory interleukin 6, that also signal through the gp130 receptor. supplier A66 T cell adhesion induces IL 6 in cultured astrocytes through activation of 3B1 integrin. Stretch induced IL 6 expression in endothelial cells is mediated by 5B1 integrin. Thus, two closely re lated cytokines are regulated by different integrins and in opposite directions, perhaps representing a mechanism by which astrocytes coordinate responses to pathological conditions. Neuronal BDNF and NGF are also upregulated by RGD integrin signaling, endothelial BDNF by B1 integrins, and IGF 1 by 2B1 and 11B1 integrins. Thus, compared to other neurotrophic factors, CNTF seems to be unique in being repressed by integrins. This explains its very low level of expression in the brain compared to other neurotrophic factors.<br><br> Collectively, our data suggest that the CNTF repressing integrin signaling pathway contains FAK and JNK which inhibits the transcription factor STAT3. FAK promotes FGF2 induced migration of astrocytes as expected from focal adhesions. This study extends the role of glial FAK to gene regulation. Neurons also con tain FAK and in the adult, it is important for LTP Here, JNK had a selective role in repressing CNTF whereas other major pathways downstream from FAK did not seem to be involved, i. e, ERK and p38. In contrast, FAK driven JNK and ERK both regulate FGF2 induced astroglial migration. The NF kappaB path way mediates 3B1 and 5B1 integrin stimulation of IL 6 in astrocytes and endothelial cells. These in tegrins do not regulate CNTF. Moreover, NF kappaB is downstream of integrin linked kinase, which associates with B1 and B3 integrins, neither one of which regu lates CNTF.