Leptin Signaling Pathways 

 Leptin regulation of GnRHR through three potential pathways. JAK2 phosphorylation activates PI3K and mTOR-mediated mRNA translation. pJAK2 also activates MAPK signaling, leading to both transcriptional and translational regulation. pSTAT3 dimerizes and enters the nucleus as a transcriptional regulator to potentially regulate miRNA or Musashi mRNA (Msi). Translational control of GnRHR may occur via miRNAs and/or Musashi. These will be tested in Aim 2 studies. Red lines show points where an inhibitor can block activation of an element in the pathway. These inhibitors will be tested in Aim 1 studies. Dotted lines suggest pathways that have yet to be proved.  See next Figure for a more detailed map of GnRHR 3’UTR.    

Murine Gnrhr 3’ UTR of mRNA.  Map showing binding element for Musashi (MBE) and miRNAs. Twenty-seven (27) miRNAs target the murine Gnrhr 3’ UTR (178 nucleotides) and map shows 17/27. Several hit the same target sites. Shown in red are miRNA target sites shared with the human Gnrhr mRNA 3’ UTRs. The MBE is flanked by these two miRNAs (miR-581/669d and miR-3061-3p). Both Musashi and miR-581/669 are increased significantly in mutant females . Curiously, miR-1199 overlaps the MBE but relevance is unclear.    

© Gwen Childs Jones, Ph.D. 1995