Many expected pathways were identified including HIF mediated hyp

Many expected pathways were identified including HIF mediated hypoxia signaling, VEGF signaling, the NRF2 mediated oxidative stress response pathway and others. Together with the pathway analysis in the forebrain, the results indicate that insulin like growth fac tor 1, glucocorticoid receptor signaling and the vitamin D3 receptor retinoid X receptor sig naling play important roles in both the cerebellum and hippocampus. However, each of these pathways has engaged different sets of genes in cerebellum compared to hippocampus and other brain regions. Genes in other pathways, such as the integrin signaling and protein ubi quitination pathways, were exclusively up regulated Inhibitors,Modulators,Libraries only in cerebellum.

It is notable that inflam mation related Inhibitors,Modulators,Libraries signaling is also represented in these cere bellum specific, hypoxia regulated genes including Fcg receptor mediated phagocytosis signaling, interleukin 8 and IL 12 signaling. Hypoxia regulated, cerebellum specific HNF4A target genes According to the above pathway analysis, transcription factors, including glucocorticoid receptor, estrogen receptor and VDR RXR, along with HIF played signifi cant roles in mediating the cerebellum region unique gene expression responses, though Inhibitors,Modulators,Libraries this did not explain the entire cerebellum specific response. To further address this question, the 1,241 transcripts up regulated only in cerebellum with at least 1. 2 fold change were subjected to network analysis in the Inge nuity Knowledge Database.

Remarkably, the transcrip tion factor hepatic nuclear receptor 4A was the hub molecule for a large network that exhibited pro tein DNA interactions with the genes corresponding to 186 transcripts up regulated only in cerebellum but not in hippocampus. The genes represented by the 186 transcripts are all verified Inhibitors,Modulators,Libraries HNF4A target genes using ChIP on chip. The presence of such a large number of HNF4A target genes in the given list of cerebellum unique genes was statistically significant. In contrast, only 23 HNF4A potential target genes were up regulated by hypoxia in both cerebellum and hippocampus. As the whole cerebellum was used in our current study, we sought evidence for the cellular localization of HNF4A using the Allen Mouse Brain Atlas. A picture from this atlas shows HNF4A mRNA in most if not all Pur kinje cells of the cerebellum and in scattered cells in the granule cell layers.

HNF4A expression is almost absent in the molecular layers and in Inhibitors,Modulators,Libraries the deep nuclei of cerebellum. This restricted expres sion in a minority of the cells in cerebellum may explain the failure to detect HNF4A mRNA in whole cerebellum using RT PCR or on microarrays or in our current method study. HNF4A mRNA in situ hybridization has yet to be done in hypoxic cerebellum where cellular localization might change considerably.

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