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Higher LST in CTC were independent of CTC enumerated, clinically more indicative of aggressive behavior than co-occurring TSG losses, and molecularly associated to gains in chromosomal regions including PTK2, Myc and NCOA2, increased androgen receptor (AR) expression, and BRCA2 loss. In 57 patients with matched cell-free tumor DNA (ctDNA) data, CTC were more frequently detectable and evaluable for CNA analysis (in 73.7% vs 42.1%, respectively). CONCLUSIONS Our findings suggest that genomic instability in CTC is a hallmark of advanced prostate cancer aggressiveness, and support single-CTC sequencing as a compelling tool to non-invasively characterize cancer heterogeneity. Copyright ©2020, American Association for Cancer Research.Mammalian oocytes are arrested at G2/prophase of the first meiosis. After a hormone surge, oocytes resume meiosis, undergoing germinal vesicle breakdown (GVBD). This process is regulated by Cdk1/cyclin B1. Here, we report that Mis12 is required for G2/M transition by regulating cyclin B1 accumulation via Cdc14B-mediated APC/CCdh1 regulation, but is not essential for spindle and chromosome dynamics during meiotic maturation. Depletion of Mis12 severely compromised GVBD by impairing cyclin B1 accumulation. Importantly, impaired GVBD after Mis12 depletion was rescued not only by overexpressing cyclin B1 but also by depleting Cdc14B or Cdh1. Notably, oocytes rescued by cyclin B1 overexpression exhibited normal spindle and chromosome organization with intact kinetochore-microtubule attachments. In addition, after being rescued by cyclin B1 overexpression, Mis12-depleted oocytes normally extruded polar bodies. Moreover, Mis12-depleted oocytes formed pronuclear structures after fertilization but failed to develop beyond zygotes. Interestingly, Mis12 was localized in the cytoplasm and spindle poles in oocytes, in contrast to kinetochore localization in somatic cells. Therefore, our results demonstrate that Mis12 is required for meiotic G2/M transition but is dispensable for meiotic progression through meiosis I and II. © 2020. Published by The Company of Biologists Ltd.Runx1 is a transcription factor that plays a key role in determining the proliferative and differential state of multiple cell types, during both development and adulthood. Here, we report how Runx1 is specifically upregulated at the injury site during zebrafish heart regeneration, and that absence of runx1 results in increased myocardial survival and proliferation, and overall heart regeneration, accompanied by decreased fibrosis. NVP-BGT226 supplier Using single cell sequencing, we found that the wild-type injury site consists of Runx1-positive endocardial cells and thrombocytes that induce expression of smooth muscle and collagen genes. Both these populations cannot be identified in runx1 mutant wounds that contain less collagen and fibrin. The reduction in fibrin in the mutant is further explained by reduced myofibroblast formation and upregulation of components of the fibrin degradation pathway, including plasminogen receptor annexin 2A as well as downregulation of plasminogen activator inhibitor serpine1 in myocardium and endocardium, resulting in increased levels of plasminogen. Our findings suggest that Runx1 controls the regenerative response of multiple cardiac cell types and that targeting Runx1 is a novel therapeutic strategy for inducing endogenous heart repair. © 2020. Published by The Company of Biologists Ltd.A crucial step in vertebrate muscle development is the activation of myogenic regulatory factors (MRFs) that direct myogenesis. A new paper in Development investigates the roles of Fgf signalling and Tbx transcription factors in zebrafish MRF induction. We caught up with the paper's two first authors, Daniel Osborn and Kuoyu Li, and their supervisor Simon Hughes, MRC Scientist and Professor of Developmental Cell Biology at King's College London, to hear more about the story. © 2020. Published by The Company of Biologists Ltd.The vomeronasal organ (VNO) contains two main types of vomeronasal sensory neurons (VSNs) that express distinct vomeronasal receptor (VR) genes and localize to specific regions of the neuroepithelium. Morphogenic signals are crucial in defining neuronal identity and network formation; however, if and what signals control maturation and homeostasis of VSNs is largely unexplored. Here, we found transforming growth factor β (TGFβ) and bone morphogenetic protein (BMP) signal transduction in postnatal mice, with BMP signaling being restricted to basal VSNs and at the marginal zones of the VNO the site of neurogenesis. Using different Smad4 conditional knockout mouse models, we disrupted canonical TGFβ/BMP signaling in either maturing basal VSNs (bVSNs) or all mature VSNs. Smad4 loss of function in immature bVSNs compromises dendritic knob formation, pheromone induced activation, correct glomeruli formation in the accessory olfactory bulb (AOB) and survival. However, Smad4 loss of function in all mature VSNs only compromises correct glomeruli formation in the posterior AOB. Our results indicate that Smad4-mediated signaling drives the functional maturation and connectivity of basal VSNs. © 2020. Published by The Company of Biologists Ltd.The Hippo pathway is a highly conserved signalling pathway that regulates multiple biological processes, including organ size control and cell fate. Since its discovery, genetic and biochemical studies have elucidated several key signalling steps important for pathway activation and deactivation. In recent years, technical advances in microscopy and genome modification have allowed new insights into Hippo signalling to be revealed. These studies have highlighted that the nuclear-cytoplasmic shuttling behaviour of the Hippo pathway transcriptional co-activators Yorkie, YAP and TAZ is far more dynamic than previously appreciated, and YAP and TAZ are also regulated by liquid-liquid phase separation. Here, we review our current understanding of Yorkie, YAP and TAZ regulation, with a focus on recent microscopy-based studies. © 2020. Published by The Company of Biologists Ltd.How much evolutionary change in development do we expect? In this Spotlight, we argue that, as developmental biologists, we are in a prime position to contribute to the definition of a null hypothesis for developmental evolution in other words, a hypothesis for how much developmental evolution we expect to observe over time. Today, we have access to an unprecedented array of developmental data from across the tree of life. Using these data, we can now consider development in the light of evolution, and vice versa, more deeply than ever before. As we do this, we may need to re-examine previous assumptions that appeared to serve us well when data points were fewer. Specifically, we think it is important to challenge assumptions that change is very rare for all developmental traits, especially if this assumption is used to sustain an erroneous view that evolution always optimizes adaptive traits toward increasing complexity. © 2020. Published by The Company of Biologists Ltd.
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