The TRIM-NHL protein TRIM32 activates microRNAs and prevents self-renewal in mouse neural progenitors

In the mouse neocortex, neural progenitor cells generate both differentiating neurons and daughter cells that maintain progenitor fate. Here, we show that the TRIM-NHL protein TRIM32 regulates protein degradation and microRNA activity to control the balance between those two daughter cell types. In both horizontally and vertically dividing progenitors, TRIM32 becomes polarized in mitosis and is concentrated in one of the two daughter cells. TRIM32 overexpression induces neuronal differentiation while inhibition of TRIM32 causes both daughter cells to retain progenitor cell fate. TRIM32 ubiquitinates and degrades the transcription factor c-Myc but also binds Argonaute-1 and thereby increases the activity of specific microRNAs. We show that Let-7 is one of the TRIM32 targets and is required and sufficient for neuronal differentiation. TRIM32 is the mouse ortholog of Drosophila Brat and Mei-P26 and might be part of a protein family that regulates the balance between differentiation and proliferation in stem cell lineages

Oxidative metabolism drives immortalization of neural stem cells during tumorigenesis

Metabolic reprogramming is a key feature of many cancers, but how and when it contributes to tumorigenesis remains unclear. Here we demonstrate that metabolic reprogramming induced by mitochondrial fusion can be rate-limiting for immortalization of tumor-initiating cells (TICs) and trigger their irreversible dedication to tumorigenesis. Using single-cell transcriptomics, we find that Drosophila brain tumors contain a rapidly dividing stem cell population defined by upregulation of oxidative phosphorylation (OxPhos). We combine targeted metabolomics and in vivo genetic screening to demonstrate that OxPhos is required for tumor cell immortalization but dispensable in neural stem cells (NSCs) giving rise to tumors. Employing an in vivo NADH/NAD(+) sensor, we show that NSCs precisely increase OxPhos during immortalization. Blocking OxPhos or mitochondrial fusion stalls TICs in quiescence and prevents tumorigenesis through impaired NAD(+) regeneration. Our work establishes a unique connection between cellular metabolism and immortalization of tumor-initiating cells

Evolving intentions for social interaction: from entrainment to joint action

This article discusses four different scenarios to specify increasingly complex mechanisms that enable increasingly flexible social interactions. The key dimension on which these mechanisms differ is the extent to which organisms are able to process other organisms' intentions and to keep them apart from their own. Drawing on findings from ecological psychology, scenario 1 focuses on entrainment and simultaneous affordance in ‘intentionally blind’ individuals. Scenario 2 discusses how an interface between perception and action allows observers to simulate intentional action in others. Scenario 3 is concerned with shared perceptions, arising through joint attention and the ability to distinguish between self and other. Scenario 4 illustrates how people could form intentions to act together while simultaneously distinguishing between their own and the other's part of a joint action. The final part focuses on how combining the functionality of the four mechanisms can explain different forms of social interactions. It is proposed that basic interpersonal processes are put to service by more advanced functions that support the type of intentionality required to engage in joint action, cultural learning, and communication

Conserved Domains of the Nullo Protein Required for Cell-Surface Localization and Formation of Adherens Junctions

During cellularization, the Drosophila melanogaster embryo undergoes a transition from syncytial to cellular blastoderm with the de novo generation of a polarized epithelial sheet in the cortex of the embryo. This process couples cytokinesis with the establishment of apical, basal, and lateral membrane domains that are separated by two spatially distinct adherens-type junctions. In nullo mutant embryos, basal junctions fail to form at the onset of cellularization, leading to the failure of cleavage furrow invagination and the generation of multinucleate cells. Nullo is a novel protein that appears to stabilize the initial accumulation of cadherins and catenins as they form a mature basal junction. In this article we characterize a nullo homologue from D. virilis and identify conserved domains of Nullo that are required for basal junction formation. We also demonstrate that Nullo is a myristoylprotein and that the myristate group acts in conjunction with a cluster of basic amino acids to target Nullo to the plasma membrane. The membrane association of Nullo is required in vivo for its role in basal junction formation and for its ability to block apical junction formation when ectopically expressed during late cellularization