Beschreibung:
Abstract: Mutations in Mecp2 gene leads to classical Rett syndrome, which is a complex genetic and progressive neurodevelopmental disorder. However, mutations in Cdkl5, Mef2c and Foxg1 cause a less frequent form called atypical Rett syndrome or Rett-like syndrome. Forkhead box binding protein 1 (FOXG1) is an important transcription factor for proper forebrain development. FOXG1 controls the neural cell fate determination and maintains the balance between progenitor cell proliferation and neuronal differentiation. In this project, FOXG1 is found to regulate the biogenesis of miR-200b/a/429 family members through its interaction with the ATP-dependent RNA helicase, DDX5/p68. FOXG1 and DDX5 associate with the microprocessor complex in both in vitro (N2a cells) and in vivo (adult mouse hippocampus). Moreover, DDX5 recruits FOXG1 to DROSHA. cAMP-dependent protein kinase type II beta regulatory subunit (PRKAR2B) was identified as a target of miR-200b/429 in neural cells by analysing the RNAseq datasets from Foxg1cre/+ mouse hippocampi and N2a cells overexpressing miR-200b/a/429 family members. PRKAR2B is an inhibitory subunit of protein kinase A (PKA) which regulates the postsynaptic neuronal functions by attenuating PKA activity. Therefore, upregulation of PRKAR2B seen in Foxg1cre/+ mouse hippocampi may contribute to neuronal dysfunctions. Furthermore, FOXG1 was found to regulate PRKAR2B expression at both transcriptional and posttranscriptional levels. These results shed light on PRKAR2B and miR-200b/429 as novel therapeutic targets for FOXG1 mediated Rett syndrome.<br><br>Foxg1cre/+ mouse hippocampi RNAseq dataset and qRT-PCR validation confirms the decreased expression of Pou3f3 antisense transcript 1 (Pantr1) in Foxg1cre/+ mouse hippocampi. Pantr1 is a nuclear, long noncoding RNA (lncRNA) that does not function in cis. Pantr1 lncRNA pulldown suggests that purine rich element binding protein beta (PURβ) could be an interaction partner of Pantr1 lncRNA. PURβ is a single stranded nucleic acid binding protein that regulates replication, transcription and translation. Pantr1 lncRNA primary sequence has six potential GAA rich elements where PURβ might bind. Further experiments are in progress to decipher the molecular and biological functions of this novel Pantr1-PURβ interaction. <br>Taken together, FOXG1 could have an important role in noncoding RNA expression and function in the CNS, which warrants in depth analyses of noncoding RNAs that are regulated by FOXG1 to ascertain their function in forebrain development and FOXG1 related syndrome