Myc inhibition is effective against glioma and reveals a role for Myc in proficient mitosis.

Gliomas are the most common primary tumours affecting the adult central nervous system and respond poorly to standard therapy. Myc is causally implicated in most human tumours and the majority of glioblastomas have elevated Myc levels. Using the Myc dominant negative Omomyc, we previously showed that Myc inhibition is a promising strategy for cancer therapy. Here, we preclinically validate Myc inhibition as a therapeutic strategy in mouse and human glioma, using a mouse model of spontaneous multifocal invasive astrocytoma and its derived neuroprogenitors, human glioblastoma cell lines, and patient-derived tumours both in vitro and in orthotopic xenografts. Across all these experimental models we find that Myc inhibition reduces proliferation, increases apoptosis and remarkably, elicits the formation of multinucleated cells that then arrest or die by mitotic catastrophe, revealing a new role for Myc in the proficient division of glioma cells

The Action Mechanism of the Myc Inhibitor Termed Omomyc May Give Clues on How to Target Myc for Cancer Therapy

Recent evidence points to Myc – a multifaceted bHLHZip transcription factor deregulated in the majority of human cancers – as a priority target for therapy. How to target Myc is less clear, given its involvement in a variety of key functions in healthy cells. Here we report on the action mechanism of the Myc interfering molecule termed Omomyc, which demonstrated astounding therapeutic efficacy in transgenic mouse cancer models in vivo. Omomyc action is different from the one that can be obtained by gene knockout or RNA interference, approaches designed to block all functions of a gene product. This molecule – instead – appears to cause an edge-specific perturbation that destroys some protein interactions of the Myc node and keeps others intact, with the result of reshaping the Myc transcriptome. Omomyc selectively targets Myc protein interactions: it binds c- and N-Myc, Max and Miz-1, but does not bind Mad or select HLH proteins. Specifically, it prevents Myc binding to promoter E-boxes and transactivation of target genes while retaining Miz-1 dependent binding to promoters and transrepression. This is accompanied by broad epigenetic changes such as decreased acetylation and increased methylation at H3 lysine 9. In the presence of Omomyc, the Myc interactome is channeled to repression and its activity appears to switch from a pro-oncogenic to a tumor suppressive one. Given the extraordinary therapeutic impact of Omomyc in animal models, these data suggest that successfully targeting Myc for cancer therapy might require a similar twofold action, in order to prevent Myc/Max binding to E-boxes and, at the same time, keep repressing genes that would be repressed by Myc

Cell-type specific programs regulate the assembly and dynamics of cortical circuits

El extraordinario repertorio de comportamientos animales se basa en el preciso ensamblaje y refinamiento de conexiones sinápticas entre diferentes subtipos neuronales. Dicha especificidad, implica tanto la diversidad celular como la sináptica que, a su vez, están determinadas por programas de genes específicamente expresados en dichas células y estrictamente regulados durante el desarrollo. En virtud de la notable diversidad de tipos y patrones de conectividad, las neuronas inhibidoras son particularmente adecuadas para desempeñar papeles específicos y funcionalmente relevantes en los circuitos neuronales y, por lo tanto, configuran de forma crítica la función cortical. De acuerdo con esto, la disfunción GABAérgica está implicada en varios trastornos neurológicos y psiquiátricos. Aunque se han hecho algunos progresos hacia la comprensión de los componentes moleculares y estructurales que distinguen ampliamente las sinapsis inhibitorias y su ensamblaje, los mecanismos moleculares subyacentes a la conectividad específica de los subtipos de interneuronas son en gran parte desconocidos. En la primera parte de este trabajo se combinaron técnicas de “FACS sorting” de células y “RNA-sequencing” para investigar los cambios dinámicos en el transcriptoma de subtipos específicos de interneuronas durante etapas tempranas del desarrollo. El perfil transcripcional de dichas interneuronas reveló la existencia de programas moleculares altamente selectivos para cada tipo de interneurona cortical durante el desarrollo. A continuación, se complementaron los perfiles de expresión génica con experimentos de pérdida de función utilizando un sistema de virus y la estrategia de “protein knockdown”. Estos experimentos mostraron que, durante el desarrollo de las conexiones sinápticas, diferentes interneuronas presentan “improntas moleculares” específicas que determinan los patrones de conectividad. Comprender la relación entre el comportamiento y la función (así como la disfunción) de los circuitos inhibitorios implica descubrir no sólo los principios de organización sino también la lógica específica de la dinámica de dichos circuitos. La plasticidad neuronal dependiente de la actividad es un mecanismo fundamental a través del cual el sistema nervioso se adapta a la experiencia sensorial. Varias líneas de investigacion sugieren que las interneuronas que expresan parvalbúmina (PV+) son esenciales en este proceso, pero los mecanismos moleculares subyacentes a la influencia de la experiencia en la plasticidad de las interneuronas siguen siendo poco conocidos. Las redes perineuronales (PNN) que envuelven las células PV+ vienen siendo las candidatas para desempeñar ese papel, pero su contribución precisa ha permanecido difícil de aclarar. En la segunda parte de la tesis, mostramos que la proteína PNN Brevican regula críticamente la plasticidad interneuronal. Encontramos que Brevican controla simultáneamente las formas celulares y sinápticas de plasticidad en interneuronas PV+ regulando, respectivamente, la localización de canales de potasio y de receptores AMPA. Al modular los niveles de Brevican, la experiencia introduce modificaciones moleculares y celulares precisas en células PV + que son necesarias para el aprendizaje y la memoria. Estos descubrimientos revelan un programa molecular a través del cual una proteína PNN facilita respuestas conductuales apropiadas a la experiencia mediante la activación dinámica de la función de interneuronas PV+

Shaping Early Networks to Rule Mature Circuits:Little MiRs Go a Long Way

Normative cortical processing depends on precise interactions between excitatory and inhibitory neurons. In this issue of Neuron, Lippi et al. (2016) identify miR-101 as a master regulator coordinating molecular programs during development that ultimately impact the activity of mature networks

Activity-Dependent Gating of Parvalbumin Interneuron Function by the Perineuronal Net Protein Brevican

Activity-dependent neuronal plasticity is a fundamental mechanism through which the nervous system adapts to sensory experience. Several lines of evidence suggest that parvalbumin (PV+) interneurons are essential in this process, but the molecular mechanisms underlying the influence of experience on interneuron plasticity remain poorly understood. Perineuronal nets (PNNs) enwrapping PV+ cells are long-standing candidates for playing such a role, yet their precise contribution has remained elusive. We show that the PNN protein Brevican is a critical regulator of interneuron plasticity. We find that Brevican simultaneously controls cellular and synaptic forms of plasticity in PV+ cells by regulating the localization of potassium channels and AMPA receptors, respectively. By modulating Brevican levels, experience introduces precise molecular and cellular modifications in PV+ cells that are required for learning and memory. These findings uncover a molecular program through which a PNN protein facilitates appropriate behavioral responses to experience by dynamically gating PV+ interneuron function

Nova proteins direct synaptic integration of somatostatin interneurons through activity-dependent alternative splicing

Somatostatin interneurons are the earliest born population of cortical inhibitory cells. They are crucial to support normal brain development and function; however, the mechanisms underlying their integration into nascent cortical circuitry are not well understood. In this study, we begin by demonstrating that the maturation of somatostatin interneurons in mouse somatosensory cortex is activity dependent. We then investigated the relationship between activity, alternative splicing, and synapse formation within this population. Specifically, we discovered that the Nova family of RNA-binding proteins are activity-dependent and are essential for the maturation of somatostatin interneurons, as well as their afferent and efferent connectivity. Within this population, Nova2 preferentially mediates the alternative splicing of genes required for axonal formation and synaptic function independently from its effect on gene expression. Hence, our work demonstrates that the Nova family of proteins through alternative splicing are centrally involved in coupling developmental neuronal activity to cortical circuit formation

Myc inhibition is effective against glioma and reveals a role for Myc in proficient mitosis

Gliomas are the most common primary tumours affecting the adult central nervous system and respond poorly to standard therapy. Myc is causally implicated in most human tumours and the majority of glioblastomas have elevated Myc levels. Using the Myc dominant negative Omomyc, we previously showed that Myc inhibition is a promising strategy for cancer therapy. Here, we preclinically validate Myc inhibition as a therapeutic strategy in mouse and human glioma, using a mouse model of spontaneous multifocal invasive astrocytoma and its derived neuroprogenitors, human glioblastoma cell lines, and patient-derived tumours both in vitro and in orthotopic xenografts. Across all these experimental models we find that Myc inhibition reduces proliferation, increases apoptosis and remarkably, elicits the formation of multinucleated cells that then arrest or die by mitotic catastrophe, revealing a new role for Myc in the proficient division of glioma cells. Myc has been implicated in the development of multiple types of cancer. Here, the authors explore the therapeutic potential and mechanism of action of Myc inhibition in mouse and human models of glioblastoma, an aggressive type of tumour that is often resistant to conventional therapy