FOXG1 Regulates PRKAR2B Transcriptionally and Posttranscriptionally via miR200 in the Adult Hippocampus

ARUMUGAM, GANESHKUMAR; HEIDRICH, STEFANIE; SANANBENESI, FARAHNAZ; SCHILLING, OLIVER; BACKOFEN, ROLF; WEISE, STEFAN C.; VIDEM, PAVANKUMAR; DUMIT, VERÓNICA I.; CRASKE, MADELINE; FISCHER, ANDRE; VILLARREAL, ALEJANDRO; NEBEL, NILS; REIMANN, VIKTORIA; HESS, WOLFGANG R.; VOGEL, TANJA

MOLECULAR NEUROBIOLOGY

HUMANA PRESS INC

Lugar: Oregon; Año: 2018

0893-7648

Rett syndrome is a complex neurodevelopmental disorder that is mainly caused by mutations in MECP2. However, mutations in FOXG1 cause a less frequent form of atypical Rett syndrome, called FOXG1 syndrome. FOXG1 is a key transcription factor crucial for forebrain development, where it maintains the balance between progenitor proliferation and neuronal differentiation. Using genome-wide small RNA sequencing and quantitative proteomics, we identified that FOXG1 affects the biogenesis of miR200b/a/429 and interacts with the ATP-dependent RNA helicase, DDX5/p68. Both FOXG1 and DDX5 associate with the microprocessor complex, whereby DDX5 recruits FOXG1 to DROSHA. RNA-Seq analyses of Foxg1cre/+ hippocampi and N2a cells overexpressing miR200 family members identified cAMP-dependent protein kinase type II-beta regulatory subunit (PRKAR2B) as a target of miR200 in neural cells. PRKAR2B inhibits postsynaptic functions by attenuating protein kinase A (PKA) activity; thus, increased PRKAR2B levels may contribute to neuronal dysfunctions in FOXG1 syndrome. Our data suggest that FOXG1 regulates PRKAR2B expression both on transcriptional and posttranscriptional levels.