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In JoVE (2)
- Generering av Stabil Transgena C. elegans Använda mikroinjektion
- Tillämpning av en C. elegans Dopamin Neuron Degeneration-analys för validering av potentiella Parkinsons sjukdomsgener
Other Publications (2)
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Articles by Laura A. Berkowitz in JoVE
JoVE General
Generering av Stabil Transgena C. elegans Använda mikroinjektion
Department of Biological Sciences, University of Alabama
Denna video visar den teknik för mikroinjektion i gonad av C. elegans för att skapa transgena djur.
JoVE General
Tillämpning av en C. elegans Dopamin Neuron Degeneration-analys för validering av potentiella Parkinsons sjukdomsgener
Department of Biological Sciences, University of Alabama
Denna video visar hur du använder C. elegans för att bedöma dopaminerga neuron neurodegeneration som modell för Parkinsons sjukdom. Dessutom är genetiska skärmar används för att identifiera faktorer som antingen ökar degeneration eller är nervskyddande.
Other articles by Laura A. Berkowitz on PubMed
SRC-1 and Wnt Signaling Act Together to Specify Endoderm and to Control Cleavage Orientation in Early C. Elegans Embryos
In early C. elegans embryos, signaling between a posterior blastomere, P2, and a ventral blastomere, EMS, specifies endoderm and orients the division axis of the EMS cell. Although Wnt signaling contributes to this polarizing interaction, no mutants identified to date abolish P2/EMS signaling. Here, we show that two tyrosine kinase-related genes, src-1 and mes-1, are required for the accumulation of phosphotyrosine between P2 and EMS. Moreover, src-1 and mes-1 mutants strongly enhance endoderm and EMS spindle rotation defects associated with Wnt pathway mutants. SRC-1 and MES-1 signal bidirectionally to control cell fate and division orientation in both EMS and P2. Our findings suggest that Wnt and Src signaling function in parallel to control developmental outcomes within a single responding cell.
The Early-onset Torsion Dystonia-associated Protein, TorsinA, is a Homeostatic Regulator of Endoplasmic Reticulum Stress Response
Early-onset torsion dystonia is the most severe heritable form of dystonia, a human movement disorder that typically starts during a developmental window in early adolescence. Deletion in the DYT1 gene, encoding the torsinA protein, is responsible for this dominantly inherited disorder, which is non-degenerative and exhibits reduced penetrance among carriers. Here, we explore the hypothesis that deficits in torsinA function result in an increased vulnerability to stress associated with protein folding and processing in the endoplasmic reticulum (ER), where torsinA is located. Using an in vivo quantitative readout for the ER stress response, we evaluated the consequences of torsinA mutations in transgenic nematodes expressing variants of human torsinA. This analysis revealed that, normally, torsinA serves a protective function to maintain a homeostatic threshold against ER stress. Furthermore, we show that the buffering capacity of torsinA is greatly diminished by the DYT1-associated deletion or mutations that prevent its translocation to the ER, block ATPase activity, or increase the levels of torsinA in the nuclear envelope versus ER. Combinations of transgenic Caenorhabditis elegans designed to mimic clinically relevant genetic modifiers of disease susceptibility also exhibit a direct functional correlation to changes in the ER stress response. Furthermore, using mouse embryonic fibroblasts (MEFs) from torsinA knockout mice, we demonstrated that loss of endogenous torsinA results in enhanced sensitivity to ER stress. This study extends our understanding of molecular mechanisms underlying dystonia, and establishes a new functional paradigm to evaluate therapeutic strategies to compensate for reduced torsinA activity in the ER as a means to restore homeostatic balance and neuronal function.
