Mutations in receptor tyrosine kinase (RTK) growth factor receptors (epidermal growth factor receptor, platelet-derived growth factor receptor, MET and ERBB2), which result in downstream activation ...of the RAS/RAF/MEK/ERK mitogen-activated protein kinase (MAPK) pathway and PI(3)K/Akt pathway, are found in almost all high-grade gliomas and MAPK signaling is necessary for continued glioma maintenance. In addition, BRAF is mutated in the majority of low-grade gliomas and its expression and activity is significantly increased in the majority of high-grade gliomas. Although the importance of RTKs and RAS signaling in glioma development has been shown, the role of BRAF has yet to be characterized. We evaluated the effect of activated BRAF in glioma formation using the retroviral replication-competent avian leukosis virus long terminal repeat, splice acceptor (RCAS)/TVA system to transfer genes encoding activated forms of BRAF, KRas, Akt and Cre to nestin-expressing neural progenitor cells in Ink4a/Arf(lox/lox) mice in vivo. Although expression of activated BRAF alone is not sufficient for tumorigenesis, the combination of activated BRAF and Akt or BRAF with Ink4a/Arf loss is transforming. Interestingly, activated BRAF generates gliomas with characteristics similar to activated KRas in the context of Akt but not Ink4a/Arf loss. Our studies show a role for BRAF activation and signaling in glioma development and as potential target for glioma therapy.
We present BonZeb-a suite of modular Bonsai packages which allow high-resolution zebrafish tracking with dynamic visual feedback. Bonsai is an increasingly popular software platform that is ...accelerating the standardization of experimental protocols within the neurosciences due to its speed, flexibility, and minimal programming overhead. BonZeb can be implemented into novel and existing Bonsai workflows for online behavioral tracking and offline tracking with batch processing. We demonstrate that BonZeb can run a variety of experimental configurations used for gaining insights into the neural mechanisms of zebrafish behavior. BonZeb supports head-fixed closed-loop and free-swimming virtual open-loop assays as well as multi-animal tracking, optogenetic stimulation, and calcium imaging during behavior. The combined performance, ease of use and versatility of BonZeb opens new experimental avenues for researchers seeking high-resolution behavioral tracking of larval zebrafish.
Animal sensory systems are tightly adapted to the demands of their environment. In the visual domain, research has shown that many species have circuits and systems that exploit statistical ...regularities in natural visual signals. The zebrafish is a popular model animal in visual neuroscience, but relatively little quantitative data is available about the visual properties of the aquatic habitats where zebrafish reside, as compared to terrestrial environments. Improving our understanding of the visual demands of the aquatic habitats of zebrafish can enhance the insights about sensory neuroscience yielded by this model system. We analyzed a video dataset of zebrafish habitats captured by a stationary camera and compared this dataset to videos of terrestrial scenes in the same geographic area. Our analysis of the spatiotemporal structure in these videos suggests that zebrafish habitats are characterized by low visual contrast and strong motion when compared to terrestrial environments. Similar to terrestrial environments, zebrafish habitats tended to be dominated by dark contrasts, particularly in the lower visual field. We discuss how these properties of the visual environment can inform the study of zebrafish visual behavior and neural processing and, by extension, can inform our understanding of the vertebrate brain.
Animals benefit from knowing if and how they are moving. Across the animal kingdom, sensory information in the form of optic flow over the visual field is used to estimate self-motion. However, ...different species exhibit strong spatial biases in how they use optic flow. Here, we show computationally that noisy natural environments favor visual systems that extract spatially biased samples of optic flow when estimating self-motion. The performance associated with these biases, however, depends on interactions between the environment and the animal's brain and behavior. Using the larval zebrafish as a model, we recorded natural optic flow associated with swimming trajectories in the animal's habitat with an omnidirectional camera mounted on a mechanical arm. An analysis of these flow fields suggests that lateral regions of the lower visual field are most informative about swimming speed. This pattern is consistent with the recent findings that zebrafish optomotor responses are preferentially driven by optic flow in the lateral lower visual field, which we extend with behavioral results from a high-resolution spherical arena. Spatial biases in optic-flow sampling are likely pervasive because they are an effective strategy for determining self-motion in noisy natural environments.
Summary
While many genetic alterations have been identified in melanoma, the relevant molecular events that contribute to disease progression are poorly understood. Most primary human melanomas ...exhibit loss of expression of the CDKN2A locus in addition to activation of the canonical mitogen‐activated protein kinase signaling pathway. In this study, we used a Cdkn2a‐deficient mouse melanocyte cell line to screen for secondary genetic events in melanoma tumor progression. Upon investigation, intrachromosomal gene amplification of Met, a receptor tyrosine kinase implicated in melanoma progression, was identified in Cdkn2a‐deficient tumors. RNA interference targeting Met in these tumor cells resulted in a significant delay in tumor growth in vivo compared with the control cells. MET expression is rarely detected in primary human melanoma but is frequently observed in metastatic disease. This study validates a role for Met activation in melanoma tumor progression in the context of Cdkn2a deficiency.
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