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

Abstract

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 Foxg1 cre/+ 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. Electronic supplementary material The online version of this article (10.1007/s12035-018-1444-7) contains supplementary material, which is available to authorized users.

The RNA helicases DDX5 and DDX17 facilitate neural differentiation of human pluripotent stem cells NTERA2

“…We also confirm the nuclear localization of DDX5 and DDX17 in both PSCs and their neural derivatives. This nuclear localization profile is also consistent with previous reports on DDX5 and DDX17 (Lamm, Nicol et al 1996, Kahlina, Goren et al 2004, Alqahtani, Gopal et al 2016, Weise, Arumugam et al 2019, whereas other RNA helicases such as DDX3 (Sekiguchi, Iida et al 2004, Vakilian, Mirzaei et al 2015 and DDX6 (Smillie andSommerville 2002, Kami, Kitani et al 2018) have been identified to mostly localize in the cytoplasm. It is yet to be determined whether DDX5 and DDX17 can possess functions in the nucleus apart from being transcriptional coregulators (Dardenne, Polay Espinoza et al 2014) and microRNA processors (Hong, Noh et al 2013, Kao, Cheng et al 2019, Weise, Arumugam et al 2019.…”

Transcription and Beyond: Delineating FOXG1 Function in Cortical Development and Disorders

“…Furthermore, Foxg1 itself has been reported to be one of the miR-200 targets in other model systems (Choi et al, 2008;Garaffo et al, 2015;Zeng et al, 2016), suggesting that FOXG1 expression levels may also be regulated through a miR-200-dependent feedback loop. RNA-seq following miR-200 overexpression and intersection of this cohort with RNA-seq datasets of the Foxg1-heterozygous hippocampus RNA-seq revealed an overlap of 35 potential target genes (Weise et al, 2019). In particular, cAMP-dependent Protein Kinase Type II-Beta Regulatory Subunit (Prkar2b) was identified as a common target for miR-200 and FOXG1 in N2a and hippocampal cells.…”

“…Further evidence that FOXG1 does not exclusively act at the chromatin comes from an interactome study which demonstrated that the fraction of FOXG1-interacting proteins in N2a cells (Weise et al, 2019) was enriched for proteins affecting post-transcriptional regulation. For example, FOXG1 associates with the microprocessor complex via interaction with DEAD Box Polypeptide 5 (DDX5), demonstrating the role of the FOXG1/DDX5 axis in miRNA biogenesis.…”

MeCP2: The Genetic Driver of Rett Syndrome Epigenetics

“…Additional development and cell-type specific co-factors regulate microprocessor activity. In addition to MeCP2, a major atypical RTT-pathogenic protein, FOXG1, is recruited to Drosha to influence miRNA biogenesis, implicating the importance of this process to RTT pathology ( Weise et al, 2019 ).…”