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Canonical TGF-β Pathway Activity is a Predictor of Medulloblastoma Survival and Delineates Putative Precursors in Cerebellar DevelopmentAref, Donya 20 November 2012 (has links)
Medulloblastoma (MB) is the most common pediatric malignant brain tumor. Little is known about aggressive forms of this disease. In order to identify pathways mediating aggressiveness in MB, we performed microarray experiments. Primary human MBs were compared to their patient matched recurrent or metastatic counterparts. Murine tumors from two MB mouse models that present with differing clinical severities were also evaluated. We identified the Transforming Growth Factor-beta (TGF-β) as a potential contributor to MB pathogenesis in both species. Smad3, a major downstream component of the TGF-β pathway, was shown to correlate with MB metastasis and survival in human tissue. Similarly, Smad3 expression during development identified a subset of cerebellar neuronal precursors as putative cells of origin for the Smad3 positive MBs. To our knowledge, this is the first study that links TGF-β to MB pathogenesis. Our research suggests that canonical activation of this pathway leads to better prognosis for patients.
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Canonical TGF-β Pathway Activity is a Predictor of Medulloblastoma Survival and Delineates Putative Precursors in Cerebellar DevelopmentAref, Donya 20 November 2012 (has links)
Medulloblastoma (MB) is the most common pediatric malignant brain tumor. Little is known about aggressive forms of this disease. In order to identify pathways mediating aggressiveness in MB, we performed microarray experiments. Primary human MBs were compared to their patient matched recurrent or metastatic counterparts. Murine tumors from two MB mouse models that present with differing clinical severities were also evaluated. We identified the Transforming Growth Factor-beta (TGF-β) as a potential contributor to MB pathogenesis in both species. Smad3, a major downstream component of the TGF-β pathway, was shown to correlate with MB metastasis and survival in human tissue. Similarly, Smad3 expression during development identified a subset of cerebellar neuronal precursors as putative cells of origin for the Smad3 positive MBs. To our knowledge, this is the first study that links TGF-β to MB pathogenesis. Our research suggests that canonical activation of this pathway leads to better prognosis for patients.
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The Role of MDM2 in Mouse Development and its Implication in the Pathogenesis of Cancer and Developmental DiseasesJoselyn Cruz Cruz (5929622) 10 June 2019 (has links)
<p>The tumor suppressor protein p53, encoded by Tp53 gene, is a transcription factor that regulates cell cycle arrest and apoptosis following cellular stresses that compromise DNA integrity and normal cellular function. Tp53 is mutated in approximately 50% of human cancers, thereby allowing cancer cells to replicate uncontrollably. In cancers in which Tp53 is not mutated, p53 is frequently functionally inactivated through other mechanisms. For example, Mdm2, a proximal negative regulator p53 is often overexpressed in cancers in which p53 is wild-type. Mdm2 is E3 ubiquitin ligase that binds to and targets p53 for proteasomal degradation and as well as inhibits p53 transcriptional activity. Pharmacological disruption of the Mdm2-p53 interaction in cancer cells with wild-type p53 is currently being explored as a strategy to enhance p53-mediated cell death in response to conventional chemotherapeutics. Nutlin-3, an Mdm2 inhibitor, promotes cell death in cultured cells from human medulloblastoma (MB), a common cerebellar pediatric cancer, suggesting that Mdm2 is a promising target to treat this tumor type. Consistent with this idea, studies in a mouse model of MB have shown that loss of Mdm2 limits the development of preneoplastic lesion in the cerebellum. The developing nature of the cerebellum in the youngest of MB patients is a major contributing factor to the side-effects resulting from current MB therapies. Studies in adult rodents suggest that nutlin-3 is non-genotoxic in normal homeostatic tissues; however the effects of nutlin-3 have not been evaluated in developing tissues. To gain insight into the potential side effects of p53 activation on the developing cerebellum, the pharmacological effects of Mdm2 inhibition in Granule Neuron Precursor cells (GNPs) was mimicked genetically using a mouse model in which Mdm2 could be selectively deleted in postnatal GNPs. My studies revealed that deletion of Mdm2 in GNPs led to a reduction in cerebellum size but did not negatively impact gross motor coordination. These results suggest that Mdm2 inhibitors may promote the killing of MB tumor cells of pediatric patients without minimal side effects on normal cerebellum development</p>
<p>In addition to cancer, p53 has an important role guarding proliferating cells during development. Activation of p53 has been implicated in the pathology of several human congenital syndromes, and mice lacking Mdm2 die in utero due to p53-mediated apoptosis. These studies highlight the need for p53 function to be tightly regulated as even modest decreases or increases in p53 function can promote cancer or disrupt normal development, respectively. During the course of my studies on Mdm2 inhibition in MB, it was serendipitously discovered that in the absence of a wild-type level of Mdm2, the phenotypic consequences of p53 activation on the developing mouse embryo were strongly influenced by the genetic background. On a 129S6/B6 F1 hybrid genetic background, mice expressing ~30% the wild-type level of Mdm2 were viable, while mice on an inbred C57BL/6 genetic background died at birth and exhibited an array of craniofacial abnormalities including coloboma, exencephaly, and cleft palate. This is the first demonstration of a role for Mdm2 in craniofacial development. The genotype-dependence, further, indicates the presence of additional genes affecting craniofacial dysmorphology. In human pleiotropic malformation syndromes, there is often clinical variability amongst individuals with an identical underlying mutation at the major effect locus. Currently, the modifier genes that influence craniofacial dysmorphology are unknown. The allelic variants encoded by the divergent genetic backgrounds that increase the penetrance and expressivity of craniofacial malformations in the Mdm2 hypomorphic mice identify the gene and protein networks governing craniofacial development. In the future, it will be important to determine the genes that are differentially expressed between mice that express low levels of Mdm2 in C57BL/6 and 129S6/B6 F1 genetic backgrounds. The results from this comparison are predicted to lead to the identification of candidate genes that influence craniofacial development through the modulation of p53 function.</p>
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The Zebrafish CerebellumKaslin, Jan, Brand, Michael 19 March 2019 (has links)
The overall architecture and cell types are highly conserved from mammals to teleost fish. The rapid transparent ex utero development in zebrafish allows direct access and precise visualization of all the major events in cerebellar development. The superficial position of the cerebellar primoridum and cerebellum further facilitates in vivo imaging of cerebellar structures and developmental events at cell resolution. Furthermore, zebrafish model have a comprehensive genetic toolbox that allow forward and reverse genetic approaches to study and manipulate gene function. Consequently, zebrafish is emerging as an excellent vertebrate model for studies of molecular, cellular and physiological mechanisms involved in cerebellar development and function at gene, cell and circuit level.
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Cerebellar Development and Neurogenesis in ZebrafishKaslin, Jan, Brand, Michael 19 March 2019 (has links)
Cerebellar organization and function have been studied in numerous species of fish. Fish models such as goldfish and weakly electric fish have led to important findings about the cerebellar architecture, cerebellar circuit physiology and brain evolution. However, most of the studied fish models are not well suited for developmental and genetic studies of the cerebellum. The rapid transparent ex utero development in zebrafish allows direct access and precise visualization of all the major events in cerebellar development. The superficial position of the cerebellar primordium and cerebellum further facilitates in vivo imaging of cerebellar structures and developmental events at single cell resolution. Furthermore, zebrafish is amenable to high-throughput screening techniques and forward genetics because of its fecundity and easy keeping. Forward genetics screens in zebrafish have resulted in several isolated cerebellar mutants and substantially contributed to the understanding of the genetic networks involved in hindbrain development (Bae et al. 2009; Brand et al. 1996). Recent developments in genetic tools, including the use of site specific recombinases, efficient transgenesis, inducible gene expression systems, and the targeted genome lesioning technologies TALEN and Cas9/CRISPR has opened up new avenues to manipulate and edit the genome of zebrafish (Hans et al. 2009; Scott 2009; Housden et al. 2016; Li et al. 2016)}. These tools enable the use of genome-wide genetic approaches, such as enhancer/exon traps and cell specific temporal control of gene expression in zebrafish. Several seminal papers have used these technologies to successfully elucidate mechanisms involved in the morphogenesis, neurogenesis and cell migration in the cerebellum (Bae et al. 2009; Chaplin et al. ; Hans et al. 2009; Volkmann et al. ; Volkmann et al. 2008). In addition, the use of genetically encoded sensors and probes that allows detection and manipulation of neuronal activity using optical methods have open up new means to study the physiology and function of the cerebellum (Simmich et al. 2012; Matsui et al. 2014). Taken together, these features have allowed zebrafish to emerge as a complete model for studies of molecular, cellular and physiological mechanisms involved in cerebellar development and function at both cell and circuit level.
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