During mouse development, the primordia of the posterior body including the trunk and tail tissues of the embryo forms largely from a bipotential cell population that resides in the posterior growth zone in vertebrate embryos. This bipotential cell population contains neuromesodermal progenitors (NMP) which are found in the tail bud which replaces the primitive streak after gastrulation and contributes to axial elongation by the formation of both the spinal cord and paraxial mesoderm derivatives. The three vertebrate Cdx genes, Cdx1, Cdx2 and Cdx4, encode transcription factors that play important roles in axial elongation since the triple Cdx mutant embryos fail to generate any tissue posterior to the occipital primordia. A comparison of Cdx mutant phenotypes suggests that Cdx2 is the most important contributor to axial elongation since Cdx2 heterozygous mutants exhibit foreshortened tails and Cdx2 conditional mutants exhibit axial truncation and complete loss of tail bud structures. Cdx2 target genes, such as Wnt3a, Cyp26a1 and T, are also essential for axial elongation. Cdx1 null mutants are viable and exhibit homeosis of cervical and anterior thoracic vertebrae, while Cdx4 null mutants are phenotypically normal. In addition, it has been shown that simultaneous loss of multiple copies of Cdx alleles disrupts axial elongation more severely than each single mutation which suggests there is overlapping function among the Cdx family. The genetic network underlying regulation of axial elongation by the Cdx family is not fully understood due in part to this functional overlap. In this thesis, I employed a conditional Cre-loxP system to derive conditional mutants lacking all Cdx functions. Additionally, Pax2-GFP transgenic mice where GFP is expressed under the control of Pax2 locus were used to enrich tail bud NMP cells for RNA-seq and ChIP-seq analysis for Cdx2. Using this approach, I revealed new target genes and pathways that are regulated by Cdx members and likely involved in axial elongation.

The products of the Cdx genes, Cdx1, Cdx2 and Cdx4, are known to play essential roles in many developmental processes including neural tube closure, axial elongation and patterning the anterior-posterior axis of the developing embryo. Cdx1 and Cdx2 are both expressed in the endoderm of the embryo and persist throughout adulthood in the intestinal epithelium, but their functions and mechanisms of action in this lineage are poorly understood, in part due to the peri-implantation lethality of Cdx2-/- mice. To circumvent this limitation, a conditional loss of function strategy was used to inactivate Cdx2 in the intestinal epithelium. These conditional mutants were also crossed to Cdx1-/- mice, which are viable and fertile, to examine potential functional compensation between these family members. The major findings of this study are that Cdx2 regulates patterning and differentiation of the small intestinal epithelium, while Cdx1 does not appear to make a contribution to either process. Furthermore, Cdx operates upstream of Notch ligand Delta-like 1 (Dll1) in endoderm and mesoderm derivatives, demonstrating that Cdx function is similar in different lineages. Finally, Cdx2 cannot fulfill the requirement for Cdx1 in regulation of its own promoter in the intestine. This is the first in vivo evidence that these two family members have context-dependent functional specificity. Altogether, this study underscores critical roles and mechanisms of action for Cdx members in the developing intestine and mesoderm.

The products of the Cdx genes, Cdx1, Cdx2 and Cdx4, are known to play essential roles in many developmental processes including neural tube closure, axial elongation and patterning the anterior-posterior axis of the developing embryo. Cdx1 and Cdx2 are both expressed in the endoderm of the embryo and persist throughout adulthood in the intestinal epithelium, but their functions and mechanisms of action in this lineage are poorly understood, in part due to the peri-implantation lethality of Cdx2-/- mice. To circumvent this limitation, a conditional loss of function strategy was used to inactivate Cdx2 in the intestinal epithelium. These conditional mutants were also crossed to Cdx1-/- mice, which are viable and fertile, to examine potential functional compensation between these family members. The major findings of this study are that Cdx2 regulates patterning and differentiation of the small intestinal epithelium, while Cdx1 does not appear to make a contribution to either process. Furthermore, Cdx operates upstream of Notch ligand Delta-like 1 (Dll1) in endoderm and mesoderm derivatives, demonstrating that Cdx function is similar in different lineages. Finally, Cdx2 cannot fulfill the requirement for Cdx1 in regulation of its own promoter in the intestine. This is the first in vivo evidence that these two family members have context-dependent functional specificity. Altogether, this study underscores critical roles and mechanisms of action for Cdx members in the developing intestine and mesoderm.

The products of the Cdx genes, Cdx1, Cdx2 and Cdx4, are known to play essential roles in many developmental processes including neural tube closure, axial elongation and patterning the anterior-posterior axis of the developing embryo. Cdx1 and Cdx2 are both expressed in the endoderm of the embryo and persist throughout adulthood in the intestinal epithelium, but their functions and mechanisms of action in this lineage are poorly understood, in part due to the peri-implantation lethality of Cdx2-/- mice. To circumvent this limitation, a conditional loss of function strategy was used to inactivate Cdx2 in the intestinal epithelium. These conditional mutants were also crossed to Cdx1-/- mice, which are viable and fertile, to examine potential functional compensation between these family members. The major findings of this study are that Cdx2 regulates patterning and differentiation of the small intestinal epithelium, while Cdx1 does not appear to make a contribution to either process. Furthermore, Cdx operates upstream of Notch ligand Delta-like 1 (Dll1) in endoderm and mesoderm derivatives, demonstrating that Cdx function is similar in different lineages. Finally, Cdx2 cannot fulfill the requirement for Cdx1 in regulation of its own promoter in the intestine. This is the first in vivo evidence that these two family members have context-dependent functional specificity. Altogether, this study underscores critical roles and mechanisms of action for Cdx members in the developing intestine and mesoderm.

The purpose of this thesis is to examine the nonlinear relationships between financial (and economic) variables within the field of financial econometrics. The thesis comprises two reviews of literatures, one on nonlinear time series models andthe other one on term structure of interest rates, and four empirical essays on financialapplications using nonlinear modelling techniques. The first empirical essay compares different model specifications of a Markov switching CIR model on the term structure of UK interest rates. We find the least restricted model provides the best in-sample estimation results. Although models with restrictive specifications may provide slightly better out-of-sample forecasts in directional movements of the yields, the economic gains seem to be small. In the second essay, we jointly model the nominal and real term structure of the UK interest rates using a three-factor essentially affine no-arbitrage term structure model. The model-implied expected inflation rates are then used in the subsequent analysis on its nonlinear relationship with the FTSE 100 index return premiums, utilizing a smooth transition vector autoregressive model. We find the model implied expected inflation rates remain below the actual inflation rates after the independence of the Bank of England in 1997, and the recent sharp decline of the expected inflation rates may lend support to the standing ground of the central bank for keeping interest rates low. The nonlinearity test on the relationship between the FTSE 100 index return premiums and the expected inflation rates shows that there exists a nonlinear adjustment on the impact from lagged expected inflation rates to current return premiums. The third essay provides us additional insight into the nature of the aggregate stock market volatilities and its relationship to the expected returns, in a Markov switching model framework, using centuries-long aggregate stock market data from six countries (Australia, Canada, Sweden, Switzerland, UK and US). We find that the Markov switching model assuming both regime dependent mean and volatility with a 3-regime specification is capable to captures the extreme movements of the stock market which are short-lived. The volatility feedback effect that we studied on each of these six countries shows a positive sign on anticipating a high volatility regime of the current trading month. The investigation on the coherence in regimes over time for the six countries shows different results for different pairs of countries. In the last essay, we decompose the term premium of the North American CDX investment grade index into a permanent and a stationary component using a Markov switching unobserved component model. We explain the evolution of the two components in relating them to monetary policy and stock market variables. We establish that the inversion of the CDX index term premium is induced by sudden changes in the unobserved stationary component, which represents the evolution of the fundamentals underpinning the risk neutral probability of default in the economy. We find strong evidence that the unprecedented monetary policy response from the Fed during the crisis period was effective in reducing market uncertainty and helped to steepen the term structure of the CDX index, thereby mitigating systemic risk concerns. The impact of stock market volatility on flattening the term premium was substantially more robust in the crisis period. We also show that equity returns make a significant contribution to the CDX term premium over the entire sample period.

Chez les vertébrés, la neurulation représente les premiers stades de développement du système nerveux durant l'embryogenèse. Elle consiste en la formation, à partir du neuroectoderme, des premières ébauches du système nerveux. Ce processus est finement régulé par un réseau complexe de gènes et le dérèglement de l'un d'entre eux peut entraîner le développement d'une maladie congénitale. Le traitement et la prévention de ces maladies passent par le savoir et la compréhension des différents processus impliqués dans le développement du système nerveux. La souris est un bon modèle d'étude in vivo de la neurogenèse et la technologie Cre-LoxP permet de contrôler l'activation spatiotemporelle d'un transgène. Cependant, aucun modèle de souris ne cible spécifiquement la plaque postérieure durant la neurulation de l'embryon. L'enhancer intronique Cdx2NSE a été caractérisé comme capable de récapituler l'expression du gène Cdx2 dans la plaque neurale postérieure. Notre nouvelle lignée de souris transgénique Cdx2NSE-Cre est capable d'exprimer la recombinase Cre dès le jour embryonnaire 7.5 (E.7.5) dans la plaque neurale postérieure. Elle permet ainsi de cibler le tube neural avec comme limite antérieure la partie caudale du rhomboncéphale. Dans ces mêmes limites, toutes les structures dérivées des cellules de la crête neurale vont également être ciblées par notre nouveau modèle murin, ce qui en fait un très bon outil pour l'étude de la neurogenèse. Le mécanisme de régulation des protéines Cdx spécifiquement dans le neuroectoderme est à ce jour toujours méconnu. L'étude in vitro de ce même enhancer Cdx2NSE nous a permis de montrer que les trois principales voies de signalisation impliquées dans le développement neural et dans l'induction des cellules de la crête neurale, à savoir les voies FGF, BMP et Wnt canonique, sont capables d'en réguler son expression sous le contrôle du gène rapporteur de la luciférase. Enfin, différentes études suggèrent une implication des protéines Cdx dans l'induction des cellules de la crête neurale et dans la fermeture du tube neural, notamment par la régulation de Pax3. Les enhancers de la crête neurale de Pax3 NCE1 et NCE2 sont effectivement régulés par la voie Wnt-Cdx (Sanchez-Ferras et al., 2012) mais un troisième enhancer de la crête neurale (NCE3) a été également caractérisé (Dagenhardt et al., 2010). Nos résultats préliminaires en essai luciférase nous suggèrent une régulation positive de cet enhancer NCE3 par les protéines Cdx1 et Cdx2. ______________________________________________________________________________ MOTS-CLÉS DE L’AUTEUR : neurogenèse, Cdx2NSE, souris, voies de signalisation, Cdx, Pax3, NCE3

The mammalian skin provides a necessary barrier between the organism and the environment, defending against loss of water and solutes, preventing the invasion of pathogens as well as protecting against chemical and physical assault. Claudin (Cldn)-based Tight Junctions (TJs) are the main functional part of the skin barrier. In particular, Cldn6 through its cytoplasmic tail has been shown to be important for barrier function. In other to further investigate the role of the Cldn6 tail in TJ-function, we developed Cldn6 mouse mutants carrying varying truncations of the Cldn6 tail. Both of these mice present with epidermal differentiation perturbations and delayed barrier function that is repaired later in life. These studies support the importance of the tail portion of the Cldn molecules in epidermal differentiation and barrier function. In addition, both of these mouse models are useful for the study of barrier function in preterm infants and in aging, with the hope of developing novel therapeutics for the alleviation of barrier dysfunction. Cdx is a family of homeodomain (HD) transcription factors (TFs) essential for many key developmental processes. In particular, Cdx2 is important for the establishment and maintenance of posterior identity in the developing endoderm. In spite of this, only a few Cdx targets in the developing endoderm have been discovered. In addition, the interplay between Cdx and its targets within the endoderm is poorly understood. In this study, we show that the forkhead box transcription factor, Foxa2 is a Cdx2 target. We also show that Foxa2 and Cdx2 physically and genetically interact to regulate a subset of genes that are implicated in endodermal development. These studies help to further our understanding of endoderm biology with the goal of developing new strategies to diagnose and treat diseases associated with defective endoderm development.

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Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.