Oxidative stress influences cell survival and homeostasis, but the mechanisms underlying the biological effects of oxidative stress remain to be elucidated. The protein kinase MST1 (mammalian Ste20-like kinase 1) plays a major role in oxidative stress-induced cell death in primary mammalian neurons. However, the mechanisms that regulate MST1 in oxidative stress responses remain largely unknown. In the present study, we demonstrate that the protein kinase c-Abl phosphorylates MST1 at Y433, which triggers the stabilization and activation of MST1.

The Sonic hedgehog (Shh) signalling pathway plays important roles during development and in cancer. Here we report a Shh-induced epigenetic switch that cooperates with Gli to control transcription outcomes. Before induction, poised Shh target genes are marked by a bivalent chromatin domain containing a repressive histone H3K27me3 mark and an active H3K4me3 mark. Shh activation induces a local switch of epigenetic cofactors from the H3K27 methyltransferase polycomb repressive complex 2 (PRC2) to an H3K27me3 demethylase Jmjd3/Kdm6b-centred coactivator complex. We also find that non-enzymatic activities of Jmjd3 are important and that Jmjd3 recruits the Set1/MLL H3K4 methyltransferase complexes in a Shh-dependent manner to resolve the bivalent domain. In vivo, changes of the bivalent domain accompanied Shh-activated cerebellar progenitor proliferation. Overall, our results reveal a regulatory mechanism that underlies the activation of Shh target genes and provides insight into the causes of various diseases and cancers exhibiting altered Shh signalling.

Learning vocal behaviors, like speech and birdsong, is thought to rely on continued performance evaluation. Whether candidate performance evaluation circuits in the brain are sufficient to guide vocal learning is not known. Here, we test the sufficiency of VTA projections to the vocal basal ganglia in singing zebra finches, a songbird species that learns to produce a complex and stereotyped multi-syllabic courtship song during development. We optogenetically manipulate VTA axon terminals in singing birds contingent on how the pitch of an individual song syllable is naturally performed. We find that optical inhibition and excitation of VTA terminals are each sufficient to reliably guide learned changes in song. Inhibition and excitation have opponent effects on future performances of targeted song syllables, consistent with positive and negative reinforcement of performance outcomes. These findings define a central role for reinforcement mechanisms in learning vocalizations and demonstrate minimal circuit elements for learning vocal behaviors. VIDEO ABSTRACT.

Molecular and functional studies of genes in neurons in mouse models require neuron-specific Cre lines. The current available neuronal Cre transgenic or knock-in lines either result in expression in a subset of neurons or expression in both neuronal and non-neuronal tissues. Previously we identified BAF53b as a neuron-specific subunit of the chromatin remodeling BAF complexes. Using a bacteria artificial chromosome (BAC) construct containing the BAF53b gene, we generated a Cre transgenic mouse under the control of BAF53b regulatory elements. Like the endogenous BAF53b gene, we showed that BAF53b-Cre is largely neuron-specific. In both central and peripheral nervous systems, it was expressed in all developing neurons examined and was not observed in neural progenitors or glial cells. In addition, BAF53b-Cre functioned in primary cultures in a pan-neuron-specific manner. Thus, BAF53b-Cre mice will be a useful genetic tool to manipulate gene expression in developing neurons for molecular, biochemical, and functional studies.

Synapse development requires normal neuronal activities and the precise expression of synapse-related genes. Dysregulation of synaptic genes results in neurological diseases such as autism spectrum disorders (ASD). Mutations in genes encoding chromatin-remodeling factor Brg1/SmarcA4 and its associated proteins are the genetic causes of several developmental diseases with neurological defects and autistic symptoms. Recent large-scale genomic studies predicted Brg1/SmarcA4 as one of the key nodes of the ASD gene network. We report that Brg1 deletion in early postnatal hippocampal neurons led to reduced dendritic spine density and maturation and impaired synapse activities. In developing mice, neuronal Brg1 deletion caused severe neurological defects. Gene expression analyses indicated that Brg1 regulates a significant number of genes known to be involved in synapse function and implicated in ASD. We found that Brg1 is required for dendritic spine/synapse elimination mediated by the ASDassociated transcription factor myocyte enhancer factor 2 (MEF2) and that Brg1 regulates the activity-induced expression of a specific subset of genes that overlap significantly with the targets of MEF2. Our analyses showed that Brg1 interacts with MEF2 and that MEF2 is required for Brg1 recruitment to target genes in response to neuron activation. Thus, Brg1 plays important roles in both synapse development/maturation and MEF2-mediated synapse remodeling. Our study reveals specific functions of the epigenetic regulator Brg1 in synapse development and provides insights into its role in neurological diseases such as ASD. Synapses formed between axons and dendrites connect neurons and generate neural circuits that control brain functions (1). The dysregulation of synapse formation, maturation, or plasticity causes many neurodevelopmental diseases such as autism (2). Autism spectrum disorders (ASDs) are complex diseases characterized by a range of behavior abnormalities and regulated by genetic and epigenetic factors (3-5). In ASDs with various genetic or environmental causes, synaptic dysfunction is a central defect.Many autism risk genes encode transcription factors and epigenetic regulators, which likely function to regulate the expression of synaptic genes (4, 6, 7). A gene network analysis predicted the core subunit of a SWI/SNF-like BRG1-associated factor (BAF) ATP-dependent chromatin remodeling complex, Brg1/SmarcA4, as one of the key nodes in autism pathogenesis (7). BAF complexes containing the ATPase Brg1 or Brm use energy derived from ATP hydrolysis to modulate chromatin structures and regulate transcription (8-10). Mutations in several BAF subunits are the genetic causes of Coffin-Siris syndrome and Nicolaides-Baraitser syndrome with autistic symptoms such as intellectual disability and delayed speech (11-15). In addition, de novo functional mutations of genes encoding several BAF subunits are identified repeatedly in autism patients (7,(16)(17)(18). Mutations in a gene encoding the BAF-associated protein activity-dependent ...