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The Hippo signaling pathway was first discovered in Drosophila melanogaster and is involved in organ size control by regulating cell proliferation and apoptosis. This well conserved pathway is activated by various signal inputs, including cell-cell contact, mechanotransduction, and G-protein coupled receptors, with signals converging on the downstream effector protein Yap and its homologue Taz, which are transcriptional co-activators. When the Hippo pathway is activated, Yap/Taz are phosphorylated, leading to cytoplasmic retention and degradation, and diminishing their transcriptional activity. Yap has also been recently implicated as a potential oncogene, as it is upregulated and transcriptionally active in several tumor types. Furthermore, inhibiting Yap activity in various cancer models has been shown to revert cancer cells to a normal phenotype. Although the role of Yap has been described in several organ systems, there is a paucity of information about the function of Yap in the central nervous system. I investigated the function of Yap/Taz in the murine cerebellum to determine its significance during normal development and a potential role for Yap/Taz in medulloblastoma, a tumor that arises in the cerebellum. In Chapter 2, I describe the expression pattern of Yap from embryonic through adult stages in mice, and demonstrate the functional significance of Yap/Taz in different cell populations using conditional knockout mouse models. I show that Yap plays a significant role in cell fate determination as well as in cerebellar foliation: Yap is highly expressed in the ventricular zone and is required for the proper formation of ependymal cells, and is also strongly expressed in Bergmann glia (BG) during early developmental stages, where Yap, together with Taz, plays a significant role in cerebellar foliation. Furthermore, Yap/Taz-deficient BG exhibit migrational defects, as their cell bodies can be found mislocalized to the molecular layer (ML), rather than remaining tightly associated with Purkinje Cells (PCs) in the PC layer. BG support the health of PCs, and severely defective BG positioning eventually leads to a loss of PCs. However, although Yap is highly expressed in granule neuron progenitors (GNPs) during the rapid postnatal expansion stage, it does not appear to play a major role in proliferation of these cells as conditionally knocking-out Yap/Taz in GNPs does not alter their proliferative capacity. Our observations demonstrate that in the cerebellum, Yap has a novel function in glia that is required for the development of normal foliation and organization, but plays a minimal role in GNP proliferation. Importantly, I also show that the reduction of sphingosine-1-phosphate G-protein-coupled receptor (S1P1) signal transduction activates the upstream kinase Lats with concomitant increases of phosphorylated Yap as well as a reduction of the known Yap target connective tissue growth factor (CTGF). This study identifies a novel function of Yap/Taz in cerebellar glia that is required for the development of normal foliation and laminar organization with sphingosine-1-phosphate (S1P) signaling as a potential extracellular cue regulating Yap activity during cerebellar development. In Chapter 3, I present further support for the finding that Yap/Taz are not required for GNP proliferation in vivo by discussing the failure of Yap/Taz loss to rescue the Sonic-hedgehog (Shh) mediated medulloblastoma phenotype, in which GNPs are considered to be the tumor cell of origin. Furthermore, I provide evidence suggestive of a tumor suppressive function of Yap/Taz in the cerebellum. Together, previously unknown functions of Yap in the developing and malignant cerebellum are described, providing a foundation for future studies of Yap in the central nervous system (CNS). / Biomedical Sciences

Submitted by Luciana Ferreira (lucgeral@gmail.com) on 2018-04-12T11:15:36Z No. of bitstreams: 2 Dissertação - Cleber Ten Caten - 2018.pdf: 2396519 bytes, checksum: f33219129581f393738906ad6922cecf (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2018-04-12T11:30:33Z (GMT) No. of bitstreams: 2 Dissertação - Cleber Ten Caten - 2018.pdf: 2396519 bytes, checksum: f33219129581f393738906ad6922cecf (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Made available in DSpace on 2018-04-12T11:30:33Z (GMT). No. of bitstreams: 2 Dissertação - Cleber Ten Caten - 2018.pdf: 2396519 bytes, checksum: f33219129581f393738906ad6922cecf (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2018-03-14 / Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPq / Traditionally, ecologists and biogeographers have been interested in ecogeographical patterns with increasing demand over the last years. Bergmann´s and Rapoport´s rules are two of the most debated ecogeographical patterns, which propose increasing in species body size and range size, respectively, with latitudes. However, whether such rules widely apply to reptiles remains unclear. Moreover, there might be uncertainty regarding the method used to obtain species geographical range that might change our perception of such patterns. Here we tested different hypotheses regarding Bergmann’s and Rapoport’s rules using the New World Pit vipers (Viperidae: Crotalinae) as biological model, as well as analyzed the robustness of different methods to obtain species geographical range and evaluated both ecogeographical patterns using different approaches. We gathered occurrence data for the 136 Crotalinae species and generated geographical ranges by building polygons from Alpha Hull method and Ecological Niche Modelling. We assessed both rules using a ‘cross-species’ and an ‘assemblage’ approach. The former considers each species as an independent data, whereas the latter consider each assemblage (i.e. a grid cell) to be an independent data. We used Phylogenetic Least Squares (PGLS) and Generalized Least Squares (GLS) to evaluate the cross-species and the assemblage pattern, respectively. The former considers the phylogenetic independence of the data as the latter the geographic autocorrelation and both provide unbiased coefficients and significance levels. Our results show that Bergmann’s rule did not occur in the cross-species level, whereas it was statistically significant in the assemblage level regardless of the method used to obtain range size. We found support for Rapoport’s rule in the cross-species level regardless of the method used to generate range size. Meanwhile, the assemblage analysis was not robust methodologically, revealing different ecogeographical patterns depending on the method used to generate species geographical range. Our findings point that there are inconsistences between the patterns observed in the cross-species and the assemblage analysis, which could indicate that different processes producing these patterns in the cross-species and assemblage levels. Finally, our results highlight that this sensibility is especially evident in Rapoport’s rule assemblage analysis and that when evaluating this pattern in assemblage level the method that will be used to obtain species geographical range should be carefully chosen. / Tradicionalmente, ecólogos e biogeógrafos tem demonstrado grande interesse por padrões ecogeográficos, especialmente durante as ultimas décadas. As regras de Bergmann e de Rapoport são dois dos padrões ecogeográficos mais debatidos, os quais propõe um aumento no tamanho corporal e na área de distribuição geográfica das espécies, respectivamente, com aumento na latitude. No entanto, ainda é incerto se repteis seguiriam essas regras. Além disso, ainda há duvida se o método utilizado para obter a área de distribuição geográfica das espécies pode afetar nossa percepção de tais padrões. No presente trabalho, testamos diferentes hipóteses em relação as regras de Bergmann e Rapoport usando os viperídeos do Novo Mundo (Viperidae: Crotalinae) como modelo biológico, além de analisarmos a robustez de diferentes métodos de obter a distribuição geográfica das espécies e avaliamos os dois padrões ecogeográficos usando diferentes abordagens. Nós reunimos dados de ocorrência para as 136 espécies de Crotalineos e geramos suas distribuições geográficas construindo polígonos utilizando o método Alpha Hull e através de modelos de nicho ecológico. Nós avaliamos ambas as regras utilizando uma abordagem interespecífica e uma de assembleia. A primeira considera cada espécie como um dado independente enquanto a segunda considera cada assembleia (i.e. célula de grid) como um dado independente. Nós utilizamos Quadrados mínimos generalizados filogenéticos (PGLS) e Quadrados mínimos generalizados (GLS) para avaliar os padrões interespecíficos e de assembleias, respectivamente. O primeiro considera a independência filogenética do dado enquanto o segundo a autocorrelação espacial e ambos fornecem coeficientes e níveis de significância não enviesados. Nossos resultados demonstram que a regra de Bergmann não ocorre a nível interespecífico, ao passo que é estatisticamente significativa em nível de assembleia e independente de como foi obtido a distribuição geográfica das espécies. Nós encontramos suporte para regra de Rapoport a nível interespecífico independente de como geramos a distribuição geográfica das espécies. Por outro lado, a analise de assembleia não foi robusta metodologicamente, revelando diferentes padrões ecogeográficos dependendo do método usado para gerar a distribuição geográfica das espécies. Nossos resultados demonstram inconsistência entre os padrões observados nas análises interespecíficas e de assembleia. Finalmente, nossos resultados ressaltam que essa sensibilidade é especialmente evidente na análise de assembleia da regra de Rapoport e que ao avaliar esse padrão em nível de assembleia o método que será usado para obter a distribuição geográfica das espécies deveria ser escolhido cuidadosamente.

Submitted by Liliane Ferreira (ljuvencia30@gmail.com) on 2018-09-03T12:14:16Z No. of bitstreams: 2 Dissertação - Juliana Silva Prado - 2018.pdf: 3426266 bytes, checksum: 8677cc417b12183a4ded6032cee7d911 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2018-09-04T11:37:20Z (GMT) No. of bitstreams: 2 Dissertação - Juliana Silva Prado - 2018.pdf: 3426266 bytes, checksum: 8677cc417b12183a4ded6032cee7d911 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Made available in DSpace on 2018-09-04T11:37:20Z (GMT). No. of bitstreams: 2 Dissertação - Juliana Silva Prado - 2018.pdf: 3426266 bytes, checksum: 8677cc417b12183a4ded6032cee7d911 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2018-02-14 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / Understanding what factors are behind human morphological variation has for many years been one of the key objectives of various research fields, namely evolutionary, genetic and anthropological biology. The morphological diversity of the human skull sparks great scientific interest, seeing as though quantitative data (due to the genetic complexity in play) showing the patterns of microevolution is useful for analyzing and understanding matters concerning the evolutionary history of populations, such as dispersal, gene flow, isolation by distance, large-scale expansion, among others. For this purpose, the use of multivariate techniques, such as Principal Component Analysis (PCA), has been supported to assess the human genetic variation on continents. Within this context, the key objective of this article was to characterize human cranial variation, utilizing PCA and Multivariate Spatial Correlation (MSC), so as to assess and identify possible evolutionary processes that contributed to the variation observed. To this end, cranial measurements available on the database obtained by W. Howells (57 variables), sourced from 1248 adult male specimens distributed throughout 30 locations (populations) in the world, were utilized. The results show that there has been spatial structuration of data, as indicated by the spatial autocorrelation statistics (Mantel Test 0.4077, P = 0.001; 59,64% of Moran's Index value with 0.05 significance and average correlogram with positive values in the first few distance bands and negative values in the subsequent bands). The use of PCA and MSC demonstrated that MSC was able to best capture the spatial pattern of data, increasing variation percentages from 54,74% to 69,33% in the first two principal components, where the techniques showed that 26 variables relative to cranial size had positive correlations in these components. The mapping and multivariate regression analyses utilizing environmental data and average dispersion age showed that the variation in the cranial size of populations followed a pattern of increase in cranial size correlated with low temperatures and recent colonization. The results obtained are consistent with Bergmann's Rule, which may thus be applied to modern humans. / Compreender quais são os fatores que estão por trás da variação morfológica humana tem sido há muitos anos um dos principais objetivos de diversas áreas de pesquisa, destacando a biologia evolutiva, genética e antropologia. A diversidade morfológica do crânio humano desperta grande interesse científico, onde o uso de dados quantitativos (devido à complexidade genética que o influencia) demostrando a atuação de processos microevolutivos, é útil para analisar e buscar compreender questões relativas a história evolutiva das populações, como eventos de dispersão genética, fluxo gênico, isolamento por distância e expansão em grande escala, dentre outros. Para tal, o uso das técnicas multivariadas, como a Análise de Componentes Principais (PCA), tem sido defendido para se avaliar a variação genética humana em regiões continentais. Nesse contexto, o objetivo central deste trabalho foi caracterizar a variação craniana humana, utilizando a PCA e a técnica de Correlação Espacial Multivariada (MSC), a fim de avaliar e identificar possíveis processos evolutivos que contribuíram para a variação observada. Para tal propósito, foram utilizadas as características métricas cranianas disponíveis no banco de dados obtido por W. Howells (57 variáveis) proveniente de 1248 espécimes adultos do sexo masculino distribuídos em 30 localidades (populações) pelo mundo. Os resultados demonstraram que houve estruturação espacial dos dados, indicado pelas estatísticas de autocorrelação espacial (Teste de Mantel 0.4077, P = 0.001; 59,64% dos índices I de Moran significativos a 0.05, e correlograma médio com valores positivos nas primeiras classes de distância e negativos nas seguintes). O uso da PCA e do MSC demonstraram que a técnica do MSC capturou melhor o padrão espacial dos dados, aumentando os valores da percentagem de variação passando de 54,74% para 69,33% nos 2 primeiros componentes principais, onde as técnicas demonstraram que 26 variáveis correspondentes a tamanho neurocraniano, possuíam correlações positivas nos dois primeiros componentes principais. Os mapas sintéticos e as análises de regressão multivariada utilizando dados ambientais e idade média de dispersão demonstraram que a variação do tamanho do crânio nas populações seguiu um padrão de aumento do tamanho craniano correlacionado a temperaturas baixas e idade de colonização recente. Os resultados obtidos são condizentes com a Regra Ecogeográfica de Bergmann, que pode então ser aplicada a humanos modernos.

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