Capítulo 3. El lugar del maestro de historia en el campo intelectual de la disciplina
1. La conceptualización de la formación docente
Overall, the data presented provide compelling evidence that NRX plays an important role as a negative regulator of Wnt signaling in F9 teratocarcinoma cells. In our model the redox regulation of NRX is imperative in controlling Wnt signaling, which would take into account the increase in the levels of ROS following RA treatment (Fig. 4.1). In this manner, the increase in ROS is predicted to modulate the conformation of NRX, thereby releasing Dvl and allowing it to participate in the transduction of the Wnt signal necessary for PrE differentiation. Although it is easy to envision that NRX serves as a failsafe mechanism to prevent aberrant Wnt signaling, the question remains as to the source of ROS. Candidates include the Nox family of ROS producing enzymes,
consisting of Nox1-4 and Duox2, that are present in F9 cells [18]. In support of this idea our lab has shown that RA-induced differentiation is hindered when F9 cells are treated with the Nox inhibitor DPI [18]. This study also revealed that the Nox1–4 and Duox2
genes are RA-responsive. Nox4 has been linked to cell proliferation, migration and stem cell differentiation [44, 45], and that the Nox1 promoter is known to be regulated by Gata6, a master regulator of ExE [46]. Furthermore, studies using intestinal cells showed overexpressing NRX blocks Wnt-induced accumulation of β-catenin, however,
overexpressing NRX and coexpressing Nox1 had the reverse effect [47]. Although these studies are encouraging and supportive, at present we do not know which of the Nox enzymes are responsible for producing the burst of ROS that is seen in F9 cells following exposure to RA.
Despite not knowing the source that produces the ROS in response to RA, it is important to note that the regulation of these levels in the cell is essential since high levels of ROS and aberrant Wnt signaling are frequently demonstrated in cancer cells [43]. This NRX related redox regulation could have significant implications in understanding Wnt-dependent carcinogenesis. Towards that end, this study not only provides insight into how extraembryonic endoderm differentiates in the mammalian embryo, but it also gives us a better understanding of the relationship between ROS and the aberrant activation of signal transduction pathways involved in human
Figure 4.1 A model for the differentiation of extraembryonic endoderm in F9 cells. RA acts through binding to RA receptors and retinoid X receptors which efficiently bind RA- response elements in the promoter regions of target genes. RA induces the expression of Nox, leading to the production of intracellular H2O2. This increase in H2O2 levels cause
NRX to form a disulfide bridge changing conformation and causing the release of bound Dvl-2. This in turn with binding of Wnt6 to the Fzd receptor causes Dvl-2 to be recruited to the plasma membrane where it acts to destabilize the destruction complex causing an increase of β-catenin in the cytosol, subsequent translocation to the nucleus where it
binds to TCF-LEF to alter gene expression necessary for differentiation to extraembryonic endoderm.
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Curriculum Vitae
Leanne Sandieson
Education
Master of Science
University of Western Ontario, London, ON 2010-2012
• Developmental Biology
Bachelor of Science
University of Waterloo, Waterloo, ON 2006-2010
• Honours Biology
Research Experience
Graduate Student 2010-2012
University of Western Ontario
• Thesis Title: Nucleoredoxin and Wnt signaling in F9 cells
Work and Volunteer Experience
Undergraduate Teaching Assistant 2010-2012
University of Western Ontario Courses:
•
Introductory Biology Lab and Tutorial• Organismal Physiology Lab and Tutorial
•
Genetics TutorialResearch Assistant for 2009-2010
Professor Mendis-Millard
University of Waterloo
Assisting with transcribing interviews for comparing biosphere reserves
Physiotherapist Assistant (Volunteer)
AIM Health Group (Waterloo) 2008
Awards
• University of Western Ontario Graduate Research Scholarship
• University of Western Ontario Faculty Dependant Scholarship