ALBERT

Description: Ferroptosis is an iron- and lipotoxicity-dependent form of regulated cell death (RCD). It is morphologically and biochemically distinct from characteristics of other cell death. This modality has been intensively investigated in recent years due to its involvement in a wide array of pathologies, including cancer, neurodegenerative diseases, and acute kidney injury. Dysregulation of ferroptosis has also been linked to various liver diseases and its modification may provide a hopeful and attractive therapeutic concept. Indeed, targeting ferroptosis may prevent the pathophysiological progression of several liver diseases, such as hemochromatosis, nonalcoholic steatohepatitis, and ethanol-induced liver injury. On the contrary, enhancing ferroptosis may promote sorafenib-induced ferroptosis and pave the way for combination therapy in hepatocellular carcinoma. Glutathione peroxidase 4 (GPx4) and system xc− have been identified as key players to mediate ferroptosis pathway. More recently diverse signaling pathways have also been observed. The connection between ferroptosis and other forms of RCD is intricate and compelling, where discoveries in this field advance our understanding of cell survival and fate. In this review, we summarize the central molecular machinery of ferroptosis, describe the role of ferroptosis in non-cancer hepatic disease conditions and discuss the potential to manipulate ferroptosis as a therapeutic strategy.

Description: The Gal4/UAS system is one of the most powerful tools for the study of cellular and developmental processes in Drosophila . Gal4 drivers can be used to induce targeted expression of dominant-negative and dominant-active proteins, histological markers, activity sensors, gene-specific dsRNAs, modulators of cell survival or proliferation, and other reagents. We describe here novel atonal-Gal4 lines that contain regions of the regulatory DNA of atonal, the proneural gene for photoreceptors, stretch receptors, auditory organ and some olfactory sensilla. During neurogenesis, the atonal gene is expressed at a critical juncture, a time of transition from progenitor cell to developing neuron. Thus, these lines are particularly well suited for the study of the transcription factors and signaling molecules orchestrating this critical transition. To demonstrate their usefulness, we focus on two visual organs, the eye and the Bolwig. We demonstrate the induction of predicted eye phenotypes when expressing the dominant-negative EGF receptor, EGFR DN , or a dsRNA against Notch, Notch RNAi , in the developing eye disc. In another example, we show the deletion of the Bolwig's organ using the proapoptotic factor Hid. Lastly, we investigate the function of the eye specification factor Eyes absent or Eya in late retinal progenitors, shortly before they begin morphogenesis. We show that Eya is still required in these late progenitors to promote eye formation, and show failure to induce the target gene atonal and consequent lack of neuron formation. This article is protected by copyright. All rights reserved.

Description: The proneural genes are fundamental regulators of neuronal development in all metazoans. A critical role of the fly proneural factor Atonal (Ato Dm ) is to induce photoreceptor neuron formation in Drosophila , whereas its murine homolog, Atonal7 Mm (aka Ath5) is essential for the development of the ganglion cells of the vertebrate eye. Here, we identify the Bombyx mori ato homolog ( ato Bm ). In a pattern strikingly reminiscent of ato Dm , the ato Bm mRNA is expressed as a stripe in the silkworm eye disc. Its DNA-binding and protein-protein interaction domain is highly homologous to the Ato Dm bHLH. Targeted expression of Ato Bm in the endogenous ato Dm pattern rescues the eyeless phenotype of the fly ato 1 mutant and its ectopic expression induces similar gain-of-function phenotypes as Ato Dm . Rescue experiments with chimeric proteins show that the non-bHLH portion of Ato Bm (N-region) can effectively substitute for the corresponding region of the fly transcription factor, even though no apparent conservation can be found at the amino acid level. On the contrary, the highly similar bHLH domain of Ato Bm cannot similarly substitute for the corresponding region of Ato Dm . Thus, the bHLH Bm domain requires the Ato Bm N-region to function effectively, whereas the bHLH Dm domain can operate well with either N-region. These findings suggest a role for the non-bHLH portion of Ato proteins in modulating the function of the bHLH domain in eye neurogenesis and implicate specific aa residues of the bHLH in this process. genesis 00:1–11, 2011. © 2011 Wiley Periodicals, Inc.

Description: The proneural genes are fundamental regulators of neuronal development in all metazoans. A critical role of the fly proneural factor Atonal (Ato Dm ) is to induce photoreceptor neuron formation in Drosophila , whereas its murine homolog, Atonal7 Mm (aka Ath5) is essential for the development of the ganglion cells of the vertebrate eye. Here, we identify the Bombyx mori ato homolog ( ato Bm ). In a pattern strikingly reminiscent of ato Dm , the ato Bm mRNA is expressed as a stripe in the silkworm eye disc. Its DNA-binding and protein-protein interaction domain is highly homologous to the Ato Dm bHLH. Targeted expression of Ato Bm in the endogenous ato Dm pattern rescues the eyeless phenotype of the fly ato 1 mutant and its ectopic expression induces similar gain-of-function phenotypes as Ato Dm . Rescue experiments with chimeric proteins show that the non-bHLH portion of Ato Bm (N-region) can effectively substitute for the corresponding region of the fly transcription factor, even though no apparent conservation can be found at the amino acid level. On the contrary, the highly similar bHLH domain of Ato Bm cannot similarly substitute for the corresponding region of Ato Dm . Thus, the bHLH Bm domain requires the Ato Bm N-region to function effectively, whereas the bHLH Dm domain can operate well with either N-region. These findings suggest a role for the non-bHLH portion of Ato proteins in modulating the function of the bHLH domain in eye neurogenesis and implicate specific aa residues of the bHLH in this process. genesis 00:1–11, 2011. © 2011 Wiley Periodicals, Inc.