Abstract
Recent reports suggest a link between positive regulation of the Hippo pathway with bipolar disorder (BD), and the Hippo pathway is known to interact with multiple other signaling pathways previously associated with BD and other psychiatric disorders. In this study, neuronal-like NT2 cells were treated with amisulpride (10 µM), aripiprazole (0.1 µM), clozapine (10 µM), lamotrigine (50 µM), lithium (2.5 mM), quetiapine (50 µM), risperidone (0.1 µM), valproate (0.5 mM), or vehicle control for 24 h. Genome-wide mRNA expression was quantified and analyzed using gene set enrichment analysis (GSEA), with genes belonging to Hippo, Wnt, Notch, TGF- β, and Hedgehog retrieved from the KEGG database. Five of the eight drugs downregulated the genes of the Hippo pathway and modulated several genes involved in the interacting pathways. We speculate that the regulation of these genes, especially by aripiprazole, clozapine, and quetiapine, results in a reduction of MAPK and NFκB pro-inflammatory signaling through modulation of Hippo, Wnt, and TGF-β pathways. We also employed connectivity map analysis to identify compounds that act on these pathways in a similar manner to the known psychiatric drugs. Thirty-six compounds were identified. The presence of antidepressants and antipsychotics validates our approach and reveals possible new targets for drug repurposing.
Highlights
The non-canonical Hippo signaling pathway, due to its diverse interplay with a variety of signaling cascades, i.e., TGF-β, Wnt, Hedgehog (HH), and Notch signaling pathways [3], has been associated with diversified mechanisms according to different microenvironments [4]: neurogenesis [5], neuronal development [6], neuronal dendritic field formation [7,8], and, more recently, neuroinflammation [9] and immunology [10]
The list of genes involved in the Hippo pathway was extracted from the Kyoto Encyclopedia of Genes and Genomes (KEGG)
Our results show that these medications modulate the Hippo signaling pathway genes, that is, they contribute to the downregulation of NF2 and WWC1 genes, accompanied by the downregulation of the Wnt and
Summary
PDZ-binding motif (TAZ) [1,2]. It was first discovered in Drosophila melanogaster, where a genetic mutation in one of its core components (Hippo/Hpo) was associated with tissue overgrowth of the eyes, wings, and limbs, a phenotype that gave name to the pathway [1]. The canonical Hippo signaling pathway is a key regulator of organ size and tissue remodeling [2]. The non-canonical Hippo signaling pathway, due to its diverse interplay with a variety of signaling cascades, i.e., TGF-β, Wnt, Hedgehog (HH), and Notch signaling pathways [3], has been associated with diversified mechanisms according to different microenvironments [4]: neurogenesis [5], neuronal development [6], neuronal dendritic field formation [7,8], and, more recently, neuroinflammation [9] and immunology [10]
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