"Read More About It" Pages - Biology 376 - Fall 2012

December 7 Presentations

Wnt/β-catenin signaling induces the aging of mesenchymal stem cells through the DNA damage response and the p53/p21 pathway

Presented by Kate Partynski

Adult mesenchymal stem cells (MSCs) are responsible for maintaining and repairing tissues such as bone, cartilage, and muscle. They have the ability to self-renew and maintain multipotency, and they are not considered as controversial to use in research as embryonic stem cells. Their use in clinical applications, therefore, is highly desirable, especially in cell and tissue transplantation therapy. However, MSCs are subject to aging like any other cell. Cellular senescence limits the lifespan of cells, which prevents them from proliferating indefinitely. While this helps to prevent cancerous cells, it also means that senescent MSCs are no longer effective in clinical therapy; older cells are not able to proliferate, deteriorate after a number of cell divisions, and eventually die of old age. Understanding the mechanism for their senescence thus becomes very important.

Previous studies suggested that upregulation of the Wnt pathway promotes senescence, but the mechanism was not understood. To better understand the effect of Wnt signaling on senescence in MSCs, Zhang et al. introduced old rat serum (ORS) to young rats and measured signs of aging in the cells. Wnt signalling/β-catenin was upregulated after injection of ORS, and dysfunctional MSCs were rescued by inhibition of Wnt signaling. Similarly, p53 and p21, genes that act to mediate senescence and tumor suppression, were upregulated in rats treated with ORS.

The results of this study suggest that upregulation of the Wnt pathway activates p53 and p21 via the DNA damage response. When Wnt signaling is upregulated in aging MSCs, p53 and p21, as tumor suppressor genes, arrest the cell cycle. The extracellular matrix, therefore, plays an important role in cellular aging of MSCs.

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CDK8 is a colorectal cancer oncogene that regulates β-catenin activity

Presented by Chelsea Zaniboni

Colorectal cancer can largely be blamed by unregulated activation of the canonical Wnt/β-catenin pathway. β-catenin as an oncogene is known to drive tumor proliferation into the colon. CDK8 is a member of the mediator complex, a transcriptional coactivator located in a region of copy number gain in a large number of colorectal cancers. Copy number gain is the result of a cell having extra copies of one or more sections of DNA. Firestein et al. conducted a study to determine whether of not CDK8 as an oncogene plays a role in β-catenin-dependent transcription and cancer proliferation

After investigating the amplified chromosome 13 in a number of colorectal cancers, CDK8 copy number gain, amplification, and over expression was observed in a substantial fraction. Suppression of the gene's expression in those cancers already characterized by high levels of CDK-8 and β-catenin activity resulted in decreased proliferation. A similar pattern was observed when §-catenin was suppressed in the same cell lines.

CDK8 was suppressed using short hairpin RNAs, resulting in reduced β-catenin-dependent transcriptional activity, and thus inhibited proliferation. This study concluded that β-catenin is directly regulated by the mediator complex which includes CDK8 and suggested that clinical targeting of CDK8 may be beneficial in β-catenin activity driven cancers.

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C-myc in the hematopoietic lineage is crucial for its angiogenic function in the mouse embryo

Presented by Erika Martinez

C-myc is a proto-oncogene that encodes a basic helix-loop-helix transcription factor and is central for the progression of many cancers in humans. It is also important in angiogenesis, which is the formation of new blood vessels from already existing vessels. This means that it is believed that c-myc functions in vascular development and in order to determine this, c-myc was deleted from certain cell lineages.

C-myc null embryos in both endothelial and hematopoietic cell lineages created two different mutants. Initially, they seemed to show normal development, but after embryonic day 12.5, the effect of the deletion of c-myc was apparent. These embryos showed severe developmental deformities since c-myc is crucial in organ development. Hematopoiesis and angiogenesis were both affected.

The results showed that c-myc is indeed necessary in the hematopoietic lineage but not for vasculogenesis. Studying c-myc and its role in the development of the vascular system is important since it plays a significant role in the growth and survival of tumors.

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Steep Differences in Wingless Signaling Trigger Myc-Independent Competitive Cell Interactions

Presented by Sarah Patzner

Wingless, a Drosophila Wnt homolog, has been known to rescue wing cells in Drosophila, because wing imaginal cells that lack Wg signalling are destroyed by apoptosis. However, wing cells have been found to be able to survive without wingless as long as they are not surrounded by Wg-responding cells. This highlights the importance of relative differences in Wingless signalling in determining cell fates. These relative differences lead to competitive cell interactions, because the "influence" of the surrounding cells can contribute to the response of imaginal disc cells. This study concludes that Wg signaling is not intrinsically required for wing cell survival but instead, survival decisions are determined by local differences in Wg signal transduction.

It was found that Myc, a well-established cell competition factor, was not required in this process. However, the participation of the negative feedback inhibitor encoded by Notum was found in the Wg signaling process. Notum was identified as an important mediator for the basis of Wg signaling-induced cell competition by suppressing the response to Wg in surrounding cells.

There was an increase in competitive behavior of axin mutant cells that acquired a relative advantage in translational potential. This finding may be applied to cancerous tumor progression in humans. Early tumor progression and the ability to overcome growth barriers may be the result of additive effects of loss of axin (or APC) and increased translational potential.

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December 3 Presentations

The Wnt/β-catenin Pathway Is Required for the Development of Leukemia Stem Cells in AML

Presented by Julia Ellison

With acute myelogenous leukemia (AML) being one of the most common leukemia cancers in adults, there is interest in finding the signal pathways that control the self-renewal capabilities in leukemia stem cells (LSCs). LSCs are responsible for the maintenance of AML and exhibit extensive proliferation and self-renewal capabilities. There are multiple pathways involved in the transformation of these cells, but the one that this study focused on was the Wnt/βcatenin pathway because although it is active in some leukemia cancers, it is not clear whether its required in AML.

In this study two different cell lines, KLS and GMP, were transformed by co-expression of Hoxa9 and Meis1a or with the fusion oncoprotien MLL-AF9. Using Immunophenotypic analysis they found that the transformation of GMP did not show the same ability in the development of leukemia. To determine which pathway was involved in LSC that was inactive in the GMP cell line, they first determined which genes were being expressed differently. They found that the genes Ptgs1 and Ptger1, which are a prostaglandin and its receptor, were up-regulated in the cells that had been successfully transformed. It is important to note that there is a connection between prostaglandin synthesis and the Wnt pathway, so they next screened the cells for activated βcatenin, and found that the leukemogenic cells exhibited active βcat. They next transduced GMP cells with βcat and found that this it did not induce leukemia. They also found that suppressing βcat expression, using indomethacin, resulted in reduced the levels of LSC. This suggests that β-catenin is required in AML development.

Overall the paper shows that β-catenin is required for Hox mediated transformation and that the lack of β-catenin in GMP cells limits their ability to initiate production of leukemia stem cells.

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Epigenetically Controlled Fibroblast Growth Factor Receptor 2 Signaling Imposes on the RAS/BRAF/Mitogen-Activated Protein Kinase Pathway to Modulate Thyroid Cancer Progression

Presented by Samantha Davenport

Cancer behavior and progression is altered by the dysregulation of growth factor signaling. One such family of growth factors that affects carcinomas is fibroblast growth factor (FGF) and fibroblast growth factor receptors (FGFR). FGF's are a family heparin binding proteins that is comprised of 23 members. Previous studies have found that FGFR expression is dysregulated in human thyroid tumors and cell lines. FGFR2 was the only FGFR found in normal thyroid tissues and it showed diminished expression in thyroid tumors. Additionally FGF1 has been found in benign and malignant thyroid tumors. There have been no mutations or rearrangements found in thyroid cancers involving FGRFs, which suggests that epigenetics are the cause of dysregulated FGFR expression in thyroid cancers. This study hypothesized that FGFR1 promotes thyroid cell growth and that FGFR2 plays a protective role against cancer progression in genetically transformed thyroid cells.

This study found that FGFR1 and FGFR2 have differing expression and actions in thyroid carcinoma. It was found that FGFR1 has cancer promoting roles, which confirmed the results found in a previous study. By siRNA knockout FGFR1 was down regulated and resulted in slowed carcinoma cell invasion and suppressed tumor growth in mice. FGFR2 on the other hand was shown to suppress cancer in thyroid cells. Expression of a particular isoform of FGFR2, FGFR2-IIIb interrupted signaling upstream of BRAF, and in turn upstream of MAPK (ERK1/2) activation in thyroid carcinoma cells and reduced tumor growth. Down regulation of FGFR2 has been linked to tumor progression, which led to the hypothesis that FGFR2 has tumor suppressive actions. This study found that forced FGFR2-IIIb expression reduced thyroid tumor progression and enhanced apoptosis.

In the normal RAS/BRAF/MAPK pathway BRAF transduces regulatory signals and is activated so that excess cell growth doesn't occur. In thyroid carcinoma tumors BRAF becomes mutated and gets phosphorylated, which results in MAPK activation. When MAPK is activated it can enter the nucleus and bind to DNA causing gene transcription and tumor cell proliferation. With FGFR2-IIIb expression in thyroid carcinoma cells BRAF phosphorylation is inhibited and therefore MAPK activation is reduced. However, not all thyroid carcinomas have BRAF mutations that induce BRAF phosphorylation. Therefore suppressive signals upstream of BRAF would offer another approach to thyroid carcinoma tumor suppression. The article suggests that FGFR2 inhibits tumor growth by appropriating limited amounts of FRS2 in order to divert signaling away from FGFR1 and other RTK's and tumor promoting pathways.

The data found in this study suggests that epigenetics may be the cause of dysregulation of FGFR2 in thyroid carcinoma tumors. FGFR2 gene silencing has been found in thyroid carcinoma cells, but more research needs to be done in order to see if that gene silencing is caused by epigenetics or some other factor.

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Cripto-1 enhances the canonical Wnt/β-catenin signaling pathway by binding to LRP5 and LRP6 co-receptors

Presented by Nikita Patel

Cripto-1, also known as teratocarinoma-derived growth factor-1 (TDGF-1), is a target gene that lies downstream of the canonical Wnt signaling pathway and is expressed in early embryos and colon cancer cells. Normally, Cripto-1 is linked to many important cellular processes, such as the development of new blood vessels and cell migration, by activating many vital cellular signaling pathways. Through the binding of the Wnt co-receptors, LRP5 and LRP6, Cripto-1 is able to modify the signaling of the canonical Wnt pathway. The LRP5 and LRP6 are transmembrane low-density lipoprotein receptors that are downstream from the family transmembrane Frizzled receptors. Cripto-1 helps phosphorylate the LRP5 and LRP6, allowing Wnt3a to easily bind to them in order for the signaling pathway to be activated even when the Wnt3a concentrations are low or limited.

Additionally, in-vitro experiments suggest that Wnt3a also enhances Cripto-1's stimulation of migration, invasion and colony formation in mice mammary epithelial cells. This overexpression can cause mammary tumors in mice. Therefore, suggesting that Wnt3a ligand causes Cripto-1 to function as an oncogene by stimulating cell proliferation. The Wnt3 proto-oncogene in mice is a paralog of the Wnt3 and Wnt3a ligand in humans as well. This paper demonstrates that Cripto-1's ability to bind to the LRP5 and LRP6 co-receptors allows it to enhance the signaling of the Wnt pathways through Wnt3, in both mice and humans, showing that these pathway interactions are as important in cancer as they are to early development.

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The Wnt/β-catenin signaling pathway targets PPARɣ activity in colon cancer cells

Presented by Sierra Ferreira

Adenocarcinoma is a type of epithelial cancer that originates in glandular tissue, like the colon. The fact that it receives less media attention than breast or prostate cancer makes it hard to believe that colon cancer is the third deadliest form of cancer among men and women, but it's the truth. Understanding the mechanics of this disease can lead to a cure that has the potential to save many lives.

In colon cancer cells, misregulation of Wnt/β-catenin signaling results in cellular proliferation. Peroxisome Proliferator-Activated Receptor-ɣ (PPARɣ) is a nuclear receptor highly expressed in the colon. It forms a heterodimer with the retinoic X receptor and binds to PPAR-responsive elements located in target gene promoters. The function of PPARɣ ligands in tumor formation is highly disputed amongst scientists. In some experiments where PPARɣ is highly expressed, tumor growth is inhibited. However, other experiments show high PPARɣ expression leads to an increase in polyp numbers. Although many polyps are simply benign, all colon cancer develops from polyps. This controversy has led to further investigation of the Wnt-signaling pathway's regulatory effect on PPARɣ in colon cells.

It has been found that APC mutation initiates the development of colon tumors. Using what we know about the Wnt-signaling pathway, we can conclude that mutations in the APC prevent degradation of β-catenin. This leads to its accumulation and translocation into the nucleus where it binds transcription factors to induce cellular proliferation. Through immunohistochemical analysis scientists found that mice with mutated APC (APCmin) contained higher levels of PPARɣ than mice with wild type APC. They also found that increased β-catenin levels resulted in increased PPARɣ levels, suggesting a link between β-catenin and PPARɣ. Although many scientists hypothesized that this link was indirect, coimmunoprecipitation showed a direct interaction between PPARɣ, β-catenin, and Tcf-4. Through experimentation with a luciferase reporter gene, it was shown that PPARɣ activity was regulated by the Wnt agonist LiCl.

The overall results of these experiments show that PPARɣ activity in colon epithelial cells is regulated by the Wnt/β-catenin signaling pathway. Misregulation of this pathway can lead to the formation of adenocarcinoma.

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November 28 Presentations

Drosophila Bcl-2 Proteins Participate in Stress-Induced Apoptosis, but Are Not Required for Normal Development

Presented by Cristel Cueto-Boutet

Programmed cell death (PCD) is an essential process in animal development, required for proper formation and maintenance of tissues during embryogenesis and beyond. The cell death mechanisms of PCD allows for the contained destruction of damaged and unwanted cells. PCD-deficient embryos result in abnormal phenotypes and embryonic lethal mutants. The molecular pathways regulating apoptosis are better understood in mammal and C. elegans models where the Bcl-2 protein family members are the principal regulators of programmed cell death. Bcl-2 proteins control the activation of caspases, proteases responsible for destroying and engulfing unwanted cells, by either direct or indirect means. Bcl-2 proteins can exhibit pro-apoptotic or anti-apoptotic functions that interact to regulate PCD pathways.

PCD is also required for Drosophila larval and adult development and where it is responsible for the proper establishment of tissues such as the nervous system and retinas as well as ensuring proper segmentation and metamorphosis, among other essential functions. The Drosophila genome contains various proteins homologous to those regulating PCD in mammals and C. elegans. Among these proteins are seven caspases and two Bcl-2 proteins: buffy and debcl. Although the Bcl-2 proteins have a central role in mammalian and C. elegans PCD and are conserved in Drosophila their specific function in apoptotic pathways, if any, was still unknown. From evidence presented in previous studies debcl is considered to be proapoptotic while buffy is thought to be antiapoptotic but have been shown to have opposite functions under special conditions.

This study sought to elucidate whether debcl and buffy exhibit similar PCD regulator functions as the Bcl-2 mammalian homologues. Through a series of exhaustive experiments the researchers demonstrated that although debcl and buffy have a limited role in DNA-damage induced apoptosis; they are not essential for embryonic development and viability as in the other models. Single and double mutants of buffy and debcl demonstrated no abnormal phenotypes. All sets of mutant specimens were developed normally (had the same number and distribution of apoptotic cells as controls, developmental patterning was unperturbed by tracking Wingless expression and hatching and other development kinetics occurred at normal rates), were fertile and viable. Through UV irradiation assays, to purposefully damaging DNA to investigate the induction of apoptosis, they were able to determine that debcl and buffy had proapoptotic and antiapoptotic functions, respectively. In a linear pathway model debcl is believed to be an upstream inhibitor of buffy, while buffy is an inhibitor of stress-induced apoptosis. There is the possibility that these Bcl-2 proteins function in separate pathways where the buffy pathway is epistatic to the proapoptotic debcl pathway. However, their roles in this pathway were not deemed as essential, but rather act as an added layer of regulation in stress-induced apoptosis. Further studies are needed to determine other apoptotic and non-apoptotic functions of buffy and debcl in Drosophila since they do not mirror mammalian or worm Bcl-2 molecular mechanics due to structural and functional differences in the PCD machinery of each group.

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The TrkC receptor induces apoptosis when the dependence receptor notion meets the neurotrophin paradigm

Presented by Kelsey Bannon

The TrkC ligand is believed to induce capase-dependent neural cell death. This form of apoptosis is mediated by caspase cleavage in vertebrates during early development when there is an absence of NT-3. The classic neurotrophic theory suggests that there are many factors which cause this neural cell death. These factors compromise nerve cell growth using the RTK pathway.

According to the neurotrophic model, cell death is believed to be triggered when there is a loss of survival signs by TrkA, TrkB, and TrkC. When these receptors are unbound, there is a preference for cell apoptosis. They are called caspase dependent receptors since they require caspase inhibitors to fully prevent apoptosis from the TrkC ligand. Caspase cleaves the TrkC protein which transforms it into a proapoptotic domain.

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Human Embryonic Stem Cells Have Constitutively Active Bax at the Golgi and Are Primed to Undergo Rapid Apoptosis

Presented by Stephen Szabo

hES - Human embryonic stem cells will undergo apoptosis if DNA damage is recognized. The apoptotic pathway by which these cells die follows a mechanism which is only recently being elucidated. Bax protein is a member of the Bcl-2 family. Bax in its activated form has been shown to be translocated to the mitochondria and induce caspase activation. Although the components of this pathway have been identified, regulation of the apoptosis pathway in primary cells is still unknown.

In this study it is shown that hES contain Bax in its active conformation localized to the Golgi apparatus. Once DNA damage is sensed Bax is moved to the mitochondria via p-53. Differentiated cells do not contain Bax in its active conformation nor is Bax localized to the Golgi. This newly elucidated mechanism of apoptosis is unique to hES cells and allows for rapid cell death of mutated cells during early embryonic development. The results also show to rapid changes in apoptitic mechanisms early in development.

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miR-29b is activated during neuronal maturation and target BH3-only genes to restrict apoptosis

Presented by Roxanne Sumanga

Apoptosis or programmed cell death is natural and crucial, especially during neural development. While programmed cell death is very important during the early stages of development, inhibition of apoptosis is just as important. The authors of this paper identify a particular mircoRNA (miR-29b), which is induced during late neurogenesis and in turn targets BH3-only genes. The BH3 gene is a subgroup of the Bcl-2 like genes, which regulates apoptosis.

miRNA is a noncoding sequence which regulates gene expression. Using microarray and quantitative RT-PCR techniques a family of miR-29 was expressed in mature neurons. However a comparison between members of the miR-29 family shows miR-29b is much heavily expressed than the other two members. Therefore further experimentation of was done using miR-29b.

miR-29b was injected into postnatal neurons at day 5 to determine if miR-29b inhibits apoptosis. Interestingly, miR-29b was able to save neurons from apoptosis despite being cultured on medium promoting cell death. Further investigation of treated neurons subject to NGF deprivation shows there is no change of expression of c-Jun phosphorylation. c-Jun phosphorylation induces BH3-only proteins. However comparison of the control to miR-29b shows a difference in cytochrome c expression. The un-injected and control neurons show faint cytochrome c staining. However in miR-29b treated neurons, cytochrome c is concentrated at the mitochondria. Therefore,miR-29b is able to inhibit apoptosis down stream from c-Jun but upstream of cytochrome c release.

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November 19 Presentations

Destruction complex function in the Wnt signaling pathway of Drosophila requires multiple interactions between Adenomatous polyposis coli 2 and Armadillo

Presented by David Banks

The destruction complex protein Adenomatous polyposis coli (APC) plays an important role in the Wnt signaling pathway (Wg in Drosophila) by binding to β-catenin (Drosophila Armadillo) and promoting its degradation in the absence of a Wnt ligand. Mutations of the APC gene lead to an unregulated Wnt pathway causing uncontrolled cell proliferation and often colorectal cancer. The process of binding APC to Armadillo is well understood in vitro but it is the goal of this paper to understand how binding works in vivo and to determine the necessary components of APC for Armadillo degradation.

To better understand how APC binds to Armadillo, McCartney et al. analyzed the two Drosophila homologs APC1 and APC2 and found that mutations that lead to loss of function and cancer are located on 20 amino acid repeats (20Rs) and are collectively known as the mutational cluster region (MCR). These repeats are Armadillo binding regions and are responsible for phosphorylation of Armadillo.

Target mutations were made in Drosophila APC2 at all five 20R regions (20R1-20R5) to determine which regions were necessary for affinity to Armadillo. There were also APC1 and APC2 knockout mutants made to determine if both or only one homolog was necessary for the binding of Armadillo.

These experiments showed that the Drosophila APC 20R3-20R5 that correspond with human APC 20R3 (which has the highest affinity for β-catenin) are not essential for the degradation of Armadillo. The researchers also showed that APC1, although expressed in a much smaller amount than APC2, is necessary for proper function of the destruction complex.

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Wnt/β-catenin signaling in the dental mesenchyme regulates incisor development by regulating Bmp4

Presented by Hana Link

The Wnt signaling pathway is key to many aspects of embryonic development, and many morphogens are controlled by it. The common mouse, Mus musculus, is a particularly useful model organism because, as a mammal, many of its developmental patterns mimic that of human development. β-catenin, a key molecule in the canonical Wnt signaling pathway, has been previously shown to affect the development of teeth in mice. In order to determine the specific role of the Wnt pathway in tooth (and specifically incisor) development, Fujimori and Novak et. al tested a variety of morphogenetic signaling proteins suspected of influencing Wnt in the dental placodes.

Tooth formation in mice occurs when the epithelium in the dental region of a day 11 embryo invaginates, and mesenchymal cells group around the invagination. Reciprocal signaling of the epithelium and mesoderm result in the formation of a tooth bud, and eventually further cell differentiation resulting in the growth of a tooth. Normal mice have a dentition including 2 incisors on each the upper and lower jaw.

Familiar proteins Fibroblast Growth Factor 8 (FGF8) and Sonic hedgehog (Shh) are secreted by the epithelium. The mesenchyme, in turn, secretes BMP4. These proteins are regulated by transcription factors controlled by the Wnt. Pathway. Experimentation found that β -catenin, when inactivated by NOGGIN or down-regulated (in the dental placode, at controlled times during development) caused the splitting of the placode into 2 separate incisor buds, resulting in an ectopic (extra, out of place) tooth. β-catenin is necessary to maintain BMP4 secretion in the mesenchyme, which subsequently upholds expression of Shh in the epithelium, resulting in the normal growth of one incisor. The number of incisors produced is controlled by β-catenin.

The effects of β-catenin and BMP4 were studied using both loss and gain of function using cre-recombinase genetic modification as well as outside effects, like an inhibitor-soaked bead. Different conditions produced different levels of phenotypic variance and numbers of incisors. The development of mouse dentition is an excellent exampled of the Wnt signaling, the morphogen sonic hedgehog, and reciprocal interaction between mesoderm and ectoderm resulting in cell differentiation and the formation of mature body structures.

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Repression of Wnt signaling by a Fer-type nonreceptor tyrosine kinase

Presented by Jessica McCarthy

The Wnt signaling pathway plays a key role in the embryonic development of many organisms and is also associated with the development of different cancers in humans. This study analyzes the Wnt signaling pathway within the model organism C. elegans, specifically looking at the regulation effects of Fer-type nonreceptor tyrosine kinase (FRK-1) within the pathway.

The researchers found that in the albescence of FRK-1, HMP-2, an ortholog of β-catenin in C. elegans that normally functions exclusively in adhesion complexes was able to continue to activate the Wnt signaling pathway by relocating to the nucleus and substituting for WRM-1. WRM-1 is responsible for signaling the induction of endoderm formation via the Wnt signaling pathway. With FRK-1 and WRM-1 knocked out, HMP-2 was able to transduce the Wnt signal and to encourage endodermic development. This showed that FRK-1 is not actually required for endodermic specification. It also showed that normally, the presence of FRK-1 is what prevents HMP-2 from transducing the Wnt signal.

APR-1 and FRK-1 are similar in that they both prevent HMP-2 from entering the nucleus and signaling the Wnt pathway. APR-1 is orthologous to the APC complex in the mammalian Wnt signaling pathway. APR-1 and FRK-1 work to prevent unnecessarily high levels of Wnt signal transduction by excluding HMP-2 β-catenin, and in doing so, preventing the formation of tumors.

This study also determined that when Wnt signaling reaches elevated levels, endoderm undergoes hyperproliferation and this results in the formation of excess gut cells in C. elegans. This excess division occurs even when POP-1 (an ortholog to Tcf/Lef transcription factors in mammals) is depleted, leading the researchers to believe that it functions in a noncanonical Wnt pathway and is not required in hyperproliferation because it occurs beyond the stage of the Wnt pathway at which β-catenin functions. The results of this study show the importance of the regulatory role that FRK-1 plays in the Wnt signaling pathway to ensure normal rates of cell division in C. elegans.

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Maternal xNorrin, a canonical wnt signaling agonist and TGF-β antagonist, controls early neuroectoderm specificiation by Xenopus

Presented by Brandon Van Seters

Wnt and BMP signaling pathways are involved in early development of Xenopus in dorsal-ventral axis specification and neuroectoderm specification. Xenopus Norrin (xNorrin) activates β-catenin in both pathways. Wnt pathway is involved by the cortical reaction results in the cortical cytoplasm shifting 30 degrees. β-catenin is stabilized in the dorsal region by presence of Dsh. This blocks the function of the GSK3 degradation complex so β-catenin accumulates and activates transcription. The presence of B-catenein induces mesoderm to become dorsal mesoderm. BMP pathway is involved when the GSK 3 complex is not inactivate and results in the absence of β-catenin. This induces mesoderm to become ventral mesoderm and secrete BMP4 to maintain ventral mesoderm.

BMP signaling pathway is involved in neuroectoderm specification by being inhibited by Noggin, Chordin, and Xnr3. Neuroectoderm is "default" for ectoderm. Noggin, Chordin and Xnr3 bind BMP4 to block receptors that induces ectoderm to become epidermal ectoderm. xNorrin is involved in inducing ectoderm to become neuroectoderm. A reciprocal inhibition of BMP4 and Norrin is necessary for embryonic ectoderm patterning.

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