DYRK1A (dual specificity tyrosine phosphorylation-regulated kinase 1A) has been shown to be involved in learning and memory impairments in Alzheimer disease and Down syndrome. As a homolog of Drosophila minibrain gene, DYRK1A also plays important roles in neurodevelopment; however, the function and regulatory mechanism of DYRK1A in neurodevelopment remain elusive. REST (RE1 silencing transcription factor) plays vital roles in neuronal differentiation. Here, we found that REST can activate DYRK1A transcription via a neuron-restrictive silencer element at bp ؊833 to ؊815 of human DYRK1A promoter. The coordinated expression of DYRK1A and REST in mouse brain further supports the cross-interaction of DYRK1A and REST during neurodevelopment. Moreover, we showed that DYRK1A dosage imbalance reduced REST protein stability and transcriptional activity through facilitating ubiquitination and subsequent degradation of REST protein. Therefore, the regulation of DYRK1A by REST in a negative feedback loop suggests that DYRK1A and REST are closely related in neurodevelopment.DYRK1A, an evolutionarily conserved and proline-directed protein kinase (1), has been shown to be involved in learning and memory impairments in Alzheimer disease and Down syndrome (DS) 2 (2). As a member of the DYRK family, DYRK1A can catalyze tyrosine-directed autophosphorylation as well as phosphorylation of serine/threonine residues in exogenous substrates. By phosphorylating the SP motif of NFAT, DYRK1A can cooperate with RCAN1 (regulator of calcineurin 1) and counteract with calcineurin in the regulation of NFAT signaling pathways (3, 4). Substrates or interacting proteins of DYRK1A comprise more than two dozen proteins including Notch, STAT3, FHKR, Gli-1, eIF2B⑀, dynamin, glycogen synthase, 14-3-3, CREB, cyclin L2, Arip4, Hip-1, PAHX-AP1, HPV16E7, and caspase 9 (6, 8 -10). The substrate diversity indicates the pleiotropic roles of DYRK1A in multiple pathways. The homolog protein of DYRK1A in Drosophila is mnb (minibrain), mutation of which caused specific defects in neurogenesis. Transgenic mice overexpressing DYRK1A exhibited delayed craniocaudal maturation with impairments in motor skill acquisition and spatial learning (11, 12). The Dyrk1a knock-out mice are embryonically lethal, and the reduced postnatal viability, small body size, and neurobehavioral abnormalities of Dyrk1a heterozygotes indicate the vital and nonredundant role of DYRK1A in neurodevelopment (13,14). However, the function and molecular mechanism of DYRK1A regulation in neurodevelopment remain elusive.REST (RE1 silencing transcription factor)/neuron-restrictive silencer factor blocks transcription of its target genes by binding to a 21-bp DNA element, RE1-binding site/neuron-restrictive silencer element (RE1/NRSE), through its eight C2H2 zinc fingers in the regulatory regions of target genes (15, 16). REST modulates expression of genes encoding fundamental neuronal functions including ion channels, synaptic proteins, and neurotransmitter receptors (15,17). Although serving as a m...
