By Jane Bradbury In this issue Samp1 makes nuclear moves FOXO3, ROS and apoptosis Diagrams of eukaryotic cells often show the nucleus in the Forkhead box O (FOXO) transcription factors induce centre of the , but the position of the nucleus actually apoptosis and regulate the production of reactive oxygen changes during certain developmental stages and cellular species (ROS). In neuronal tumour cells derived from events. For example, during the polarisation that precedes advanced stage neuroblastoma, FOXO3 – the most migration, the nucleus moves away from the prevalent FOXO in neuronal cells – is inactivated. future leading edge of the cell. This nuclear movement involves nesprin-2G (a Notably, however, chemotherapeutic agents can activate FOXO3 and spectrin repeat protein) and the SUN-domain protein SUN2, induce apoptosis in neuronal tumour cells. Judith Hagenbuchner and which are components of the linker of nucleoskeleton and (LINC) colleagues (p. 1191), who have been investigating the molecular events that complex that form transmembrane -associated nuclear (TAN) lines at the underlie FOXO3-induced apoptosis, now report that, in two neuroblastoma nuclear envelope. Now, on page 1099, Edgar Gomes and colleagues report that cell lines, FOXO3 represses mitochondrial respiration and induces cellular the nuclear envelope protein spindle-associated 1 (Samp1, ROS in response to chemotherapy. They show that etoposide- and also known as NET5 and TMEM201) is also required for nuclear movement in doxorubicin-induced elevation of cellular ROS depends on FOXO3 migrating . By using siRNA knockdown, the authors show that activation and on induction of its transcriptional target Bim (BCL2L11), a Samp1 is involved in centrosome orientation and nuclear movement during pro-apoptotic protein. Moreover, FOXO3 activation on its own induces two fibroblast polarisation and migration in wounded NIH-3T3 monolayers. They sequential ROS waves and Bim induction is essential for this phenomenon. report that Samp1 is a component of TAN lines and that it associates with both Other experiments indicate that FOXO3 also activates a ROS rescue pathway SUN2 and lamin A/C. Finally, the authors show that the maintenance of by inducing the peroxiredoxin sestrin-3. This dual effect of FOXO3 might be Samp1 at the nuclear envelope requires lamin A/C. Together, these results crucial in the control of stress sensitivity and chemotherapy-induced cell death suggest that Samp1 is involved in the regulation of the LINC complex during in neuronal tumour cells. Overall, these data identify ROS as important nuclear movement and cell migration in fibroblasts. mediators of FOXO3-induced cell death in neuronal cells.

COPIng with tracheal tube expansion Baz polarity landmark assembly The dimensions and shapes of epithelial tubules in animal The establishment and maintenance of epithelial cell organs are precisely controlled to ensure normal organ polarity is essential for animal development and function. Recent work in various model systems has physiology. In Drosophila, the scaffold protein Bazooka highlighted the importance of protein trafficking through (Baz, the fly homologue of the mammalian and worm the secretory pathway during the morphogenesis of polarity protein PAR-3) forms apical polarity landmarks epithelial systems. The expansion of the tracheal tubules in Drosophila,for that establish epithelial polarity. But how is Baz recruited to the plasma example, has been shown to depend on the trafficking of coatomer protein membrane? On page 1177, Tony Harris and co-workers propose that a complex I (COPI)-coated vesicles between the Golgi complex and the multifaceted membrane-association mechanism assembles Baz polarity endoplasmic reticulum (ER). But how is this pathway regulated? On page landmarks. Using a comprehensive structure-function approach, the authors 1318, Kristina Armbruster and Stefan Luschnig report that the Sec7 domain dissect the roles of the Baz oligomerisation domain, its three PDZ domains guanine nucleotide exchange factor protein Gartenzwerg (Garz) has an and its atypical protein kinase C and phosphoinositide lipid binding regions in essential role in epithelial tube morphogenesis and protein secretion in the cortical localisation of Baz in the Drosophila embryonic ectoderm. None Drosophila. They show that garz is required for the morphogenesis of tubular of these protein domains is essential for cortical localisation, they report. epithelia during embryogenesis, for normal Golgi morphology, and for the Instead, Baz positioning depends on multiple redundant interactions. The

Journal of Cell Science localisation of COPI components. Garz localises to the cis-Golgi complex. authors also show that the specific downstream effects of Baz localisation Moreover, genetic interaction experiments place garz in a regulatory circuit include the promotion of epithelial structure, a positive-feedback loop that that controls COPI trafficking, and overexpression of garz causes recruits other polarity proteins and a negative-feedback loop that regulates accumulation of secreted proteins in the ER. On the basis of their results, Baz. The authors propose that the recruitment of Baz to the plasma membrane the authors suggest that Garz regulates epithelial tube morphogenesis in through this new multifaceted membrane-association mechanism provides Drosophila by controlling the trafficking rate of COPI vesicles. both plasticity and robustness to Baz polarity landmarks.

Slow division route to muscle repair mAbp1 wins podosome rosette Satellite cells, which are muscle stem cells, have important Cell migration and invasion, which are fundamental to roles in postnatal muscle growth and in adult muscle many cellular processes (for example, ), regeneration. Muscle injury activates the satellite cells in require dynamic interactions between cells and the adult muscle but, interestingly, although most activated (ECM) and the capacity of cells to satellite cells divide rapidly, a few divide slowly. Now, on degrade the ECM. Some highly motile and invasive cells page 1309, Yusuke Ono and colleagues suggest that only the slowly dividing form podosomes – dynamic actin-based structures that mediate cellular satellite cells retain long-term self-renewal ability. The authors isolate satellite adhesion to the ECM and that promote localised degradation of the ECM to cells from adult mouse muscle, label them with the lipophilic dye PKH26, facilitate cell motility and invasion. Here (p. 1329), Anna Huttenlocher and co- stimulate them to divide and sort them into PKH26low fast-dividing cells and workers investigate the regulation of podosome formation and cell invasion in PKHhigh slow-dividing cells. Fast-dividing cells generate more differentiated Src-transformed fibroblasts by mammalian actin-binding protein 1 (mAbp1, and self-renewing cells than slow-dividing cells, report the authors. However, also known as DBNL), an F-actin binding protein with high structural slow-dividing cells form secondary myogenic colonies when passaged, similarity to . The authors show that mAbp1 is required for the whereas fast-dividing cells rapidly undergo myogenic differentiate without formation of podosome rosettes in Src-transformed cells, whereas cortactin is producing self-renewing cells. Notably, when transplanted into an injured required for the formation of podosome dots. Furthermore, specific Src muscle, slow-dividing cells contribute extensivelytomuscleregeneration. The phosphorylation sites in mAbp1 mediate podosome rosette formation and authors also report that only those slow-dividing cells that express high levels ECM degradation. Unexpectedly, mAbp1-deficient cells are more invasive of Id1 (a negative regulator of bHLH transcription factors) retain long-term than cells expressing mAbp1 despite forming fewer rosettes, which suggests self-renewal activity. Thus, they conclude, undifferentiated slow-dividing that mAbp1 differentially regulates ECM degradation and cell invasion. satellite cells retain ‘stemness’ and therefore might be essential for muscle Together, these results identify a role for mAbp1 in podosome rosette homeostasis throughout life. formation and cell invasion downstream of Src.