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Working within the morphosyntactic framework of Distributed Morphology (DM, Halle and Marantz 1993, 1994) within the Minimalist Program (Chomsky 1995), this dissertation proposes a new economy constraint on the grammar, MINIMIZE EXPONENCE, which selects the derivation that realizes all its interpretable features with the fewest morphemes. The purpose of this proposal is to capture the conflicting needs of the grammar to be both maximally contrastive and maximally efficient.I show that the constraint MINIMIZE EXPONENCE has a number of effects on analyses of morphosyntactic phenomena. I propose that, in order to satisfy MINIMIZE EXPONENCE, the roots in a derivation fuse with the functional heads projected above them, resulting in a simplex head that contains both a root and interpretable features. Following the tenets of DM, this head is now a target for the process of Vocabulary insertion. Since the target node contains both content and functional information, so too can Vocabulary Items (VIs) be specified for both types of information. This allows VIs such as eat and ate to compete with each other. This competition of forms linked to the same root allows for a new model of root allomorphy within the framework of DM. In this model of root allomorphy, following proposals by Pfau (2000), VIs that realize roots participate in competition in the same was as do VIs that realize abstract morphemes. Since root VIs are participating in competition and are specified for both content and formal features, the need for licensing through secondary exponence as proposed by Harley and Noyer (2000) is removed from the framework. Further, since eat and ate in this model are different VIs with different specifications that compete with each other for insertion, this model of root allomorphy also eliminates the need for readjustment rules as proposed by Halle and Marantz (1993, 1994) and elaborated on by Marantz (1997). This new model of root allomorphy allows for an account of the blocking of regular inflection in English nominal compounds (e.g. *rats-catcher), which was problematic for theorists working with DM, given the tenets of the framework.I also show that the fusion of roots and functional elements driven by MINIMIZE EXPONENCE allows for a new account of subcategorization. The model of subcategorization presented here falls out of the following facts: 1) arguments are introduced by functional heads; 2) those heads fuse with the root they are projected above, resulting in the node containing both the root and the features of the functional heads; 3) since the root now contains both the root and the formal features, the corresponding VI can be specified for both; 4) VIs that realize roots can also be specified for compatibility or incompatibility of the features of the functional heads that license argument structure. The result here is an underspecification model of subcategorization that predicts a number of behaviors of verbs with respect to their argument structure that it is difficult for a full specification model to account for. Those include polysemy (I ran the ball to Mary) and structural coercion (I thought the book to Mary).

Glioblastoma is the commonest form of brain neoplasm and among the most malignant forms of cancer. The identification of a subpopulation of self-renewing and multipotent cancer stem cells within glioblastoma has revealed a novel cellular target for the treatment of this disease. The role of developmental cell signaling pathways in these cell populations remains poorly understood. Herein, we examine the role of the Notch signaling pathway in glioblastoma stem cells. In this thesis we have demonstrated that the canonical Notch pathway is active in glioblastoma stem cells and functions to inhibit neuronal lineage commitment in a subset of patient derived glioblastoma stem cells in vitro. Gamma secretase (γ-secretase) small molecule inhibitors or dominant-negative co-activators inhibit glioblastoma stem cell proliferation and induce neuronal lineage commitment in a fashion that synergizes with Wingless pathway activation via GSK-3β blockade. Our data suggest that subsets of patient samples show a Notch gene expression profile that predicts their abilities to undergo neuronal lineage differentiation in response to γ-secretase small molecule inhibitors. Additionally, the data suggests that Notch may perturb the relative fractions of cells undergoing symmetric division, in favour of asymmetric division, limiting clonal expansion from single cells. These data may have important implications for treating human glioblastoma, and suggest that in addition to inhibition of proliferation, influencing lineage choice of the tumor stem cells may be a mechanism by which these tumors may be pharmacologically inhibited.

Glioblastoma is the commonest form of brain neoplasm and among the most malignant forms of cancer. The identification of a subpopulation of self-renewing and multipotent cancer stem cells within glioblastoma has revealed a novel cellular target for the treatment of this disease. The role of developmental cell signaling pathways in these cell populations remains poorly understood. Herein, we examine the role of the Notch signaling pathway in glioblastoma stem cells. In this thesis we have demonstrated that the canonical Notch pathway is active in glioblastoma stem cells and functions to inhibit neuronal lineage commitment in a subset of patient derived glioblastoma stem cells in vitro. Gamma secretase (γ-secretase) small molecule inhibitors or dominant-negative co-activators inhibit glioblastoma stem cell proliferation and induce neuronal lineage commitment in a fashion that synergizes with Wingless pathway activation via GSK-3β blockade. Our data suggest that subsets of patient samples show a Notch gene expression profile that predicts their abilities to undergo neuronal lineage differentiation in response to γ-secretase small molecule inhibitors. Additionally, the data suggests that Notch may perturb the relative fractions of cells undergoing symmetric division, in favour of asymmetric division, limiting clonal expansion from single cells. These data may have important implications for treating human glioblastoma, and suggest that in addition to inhibition of proliferation, influencing lineage choice of the tumor stem cells may be a mechanism by which these tumors may be pharmacologically inhibited.

Calreticulin, an endoplasmic reticulum (ER)-resident protein, is a calcium buffering chaperone. In this study, with an optimized differentiation protocol from mouse R1 ES cells, we demonstrate a novel role of calreticulin in osteogenic commitment and differentiation. To enhance the efficacy of the method, we manipulated cell density and examined the addition of retinoic acid, dexamethasone and peroxisome proliferator-activated receptor γ. The regimen consisting of seeding 250 cells per embryoid body, with the addition of RA (from day 3 to 5) and Dex (from day 10 to 21) gave the most efficacious output. Using this optimized protocol, we investigated the potential involvement of calreticulin in osteogenesis. Calreticulin knock-out cells displayed impaired osteogenesis compared to wild-type cells. In particular, the nuclear translocation of the runt-domain related transcription factor 2 and Osterix, were impaired in the absence of calreticulin. The stimulatory effect of calreticulin on osteogenesis was mediated by its calcium buffering function.

Calreticulin, an endoplasmic reticulum (ER)-resident protein, is a calcium buffering chaperone. In this study, with an optimized differentiation protocol from mouse R1 ES cells, we demonstrate a novel role of calreticulin in osteogenic commitment and differentiation. To enhance the efficacy of the method, we manipulated cell density and examined the addition of retinoic acid, dexamethasone and peroxisome proliferator-activated receptor γ. The regimen consisting of seeding 250 cells per embryoid body, with the addition of RA (from day 3 to 5) and Dex (from day 10 to 21) gave the most efficacious output. Using this optimized protocol, we investigated the potential involvement of calreticulin in osteogenesis. Calreticulin knock-out cells displayed impaired osteogenesis compared to wild-type cells. In particular, the nuclear translocation of the runt-domain related transcription factor 2 and Osterix, were impaired in the absence of calreticulin. The stimulatory effect of calreticulin on osteogenesis was mediated by its calcium buffering function.