MEF2D Regulates DYRK1A Transcription In A Negative Feedback Loop

DYRK1A, an evolutionarily conserved and praline-directed protein kinase (1), has been shown to be involved in learning and memory impairments in Alzheimer’s disease (AD) and Down Syndrome (DS)(2). DYRK1A is the mammalian homologue of the Drosophila minibrain gene (1) and is located within the HSA21q22.2Down syndrome (DS) critical region (3,4). As a member of DYRK family, DYRK1A can catalyze their autophosphorylation on tyrosine residues but phosphorylate substrates only on serine or threonine residues. By phosphorylating the SP motif of NFAT, DYRK1A can cooperate with regulator of calcineurin1(RCAN1) and counteract with calcineurin in the regulation of NFAT signaling pathways (5,6). The substrates of DYRK1A include transcription factors (FKHR/FOXO1, STAT3, CREB1), splicing factors (cyclinL2, SF3B1, SF2/ASF), protein-synthesis initiation factor eIF2Bε, the antagonist of receptor tyrosine kinase signaling SPRY2(sprouty homolog2) and proteins involved in the synapse function such as dynamin, amphiphysin, synaptojanin, a-synuclein and Hipl (7-12). Transgenic mice overexpressing DYRK1A exhibited delayed craniocaudal maturation with impairments in motor skill acquisition and spatial learning (13,14). The Dyrkla knockout mice are embryonic lethal. And the reduced postnatal viability, small body size and neurobehavioral abnormalities of Dyrkla heterozygotes indicate the vital and non-redundant role of DYRK1A in neurodevelopment (15,16). However, the function and molecular mechanism of DYRK1A regulation in neurodevelopment remain unclear.The myocyte enhancer factor2(MEF2) transcription factor plays the central roles in the transmission in extracellular signals to the genome and in the activation of the genetic programs that control cell differentiation, proliferation, morphogenesis, survival and apoptosis of a wide range of cell types (17). MEF2proteins belong to the evolutionarily ancient MADS (MCM1, agamous, deficiens, serum response factor) family of transcription factors (18). Saccharomyces cerevisiae, Drosophila and Caenorhabditis elegans possess a single Mef2gene, whereas vertebrates have four-Mef2a, b, c and d.MEF2proteins form homodimers and heterodimers that constitutively bind to response elements bearing the consensus sequence CTA(A/T)4TAG(25). The N-termini of MEF2factors contain a highly conserved MADS-box and an immediately adjacent motif termed the MEF2domain. The C-terminal regions of MEF2proteins, as the transcriptional activation domains, are subject to complex patterns of alternative splicing (19-21). Four MEF2proteins (MEF2A,-B,-C,-D)(21-25), which are encoded by distinct genes, are expressed in several tissues and cells including muscle, neurons and lymphocytes. Recent reports have showed that MEF2is regulated by kinase and calcium signaling pathways (26-29). Recent reports that cdk5can phosphorylate MEF2D, on the inactivating Serine444residue and thus inhibit its activity, its phosphorylation may induce neuronal apoptosis through the inhibition of prosurvival activity (30). Consistent with this, recent reports showed that DYRK1A was elevated in DS patients. So we think that DYRK1A may fulfill its function in neurodevelopment through its regulation of MEF2D expression.In the present study, we found MEF2D can activate DYRK1A transcription via a MEF2site at-262bp to-248bp of human DYRK1A promoter, while DYRK1A can up-regulate MEF2D protein expression and reduce its transcriptional activity, thus forming a negative feedback loop in regulation DYRK1A expression. Our study also showed that the cross-interaction between DYRK1A and MEF2D plays vital roles in the neurodevelopment.