The Notch signaling pathway is an essential cell-cell signaling pathway that is involved in cell fate decisions and cell differentiation during early metazoan development. In humans, the Notch pathway is misregulated in cancers such as T-cell acute lymphoblastic leukemia, breast cancer, lung cancer, and colorectal cancer. The key downstream effector of the Notch signaling pathway is the Notch Intracellular Domain (NICD), which is produced from a series of ligand-dependent proteolytic cleavages. Upon its liberation from the plasma membrane, NICD translocates into the nucleus and binds to the transcription factor CSL to activate a Notch-specific transcriptional program. Previous cultured cell studies suggest that regulated NICD turnover plays a critical role in regulating its steady-state intracellular levels and subsequent Notch pathway activation. Correspondingly, stabilizing mutations in NICD1 have been linked to multiple types of cancer. These results support the idea that regulation of NICD protein turnover is an essential process in regulation of Notch signaling. However, the mechanisms that control NICD degradation, and their effect on Notch signal transduction is a major unanswered question in the Notch field. We found that human NICD1 degrades robustly in a proteasome-dependent manner in Xenopus egg extract, and have identified a 35-amino acid degron (N-Box) at the N-terminus of NICD1. The N-Box is both sufficient and necessary for degradation of NICD1 in Xenopus egg extract, and, when attached to a heterologous protein in cultured human cells, promotes its turnover. Mutations in key residues within N-Box stabilize the NICD1 protein and lead to increased Notch transcriptional activity in cultured mammalian cells. We present a model as to how the N-Box may regulate NICD1 stability and transcriptional activity in the context of known stabilizing mutations of NICD1 in human cancers.

Bronchopulmonary dysplasia is a life-threatening lung disease affecting low birth weight preterm infants. While the occurrence of BPD is correlated with chorioamnionitis, the origination and pathway of fetal lung inflammation is less clear. It is unknown which cell type in the fetal lung detect pathogens and initiate inflammation. We hypothesized that fetal lung macrophages drive development-inhibiting inflammation through NF-κB activation, and that NF-κB activation alters macrophage development. While LPS normally inhibits airway branching in fetal lung explants, depleting macrophages with clodronate or inhibiting NF-κB activation in macrophages protected fetal lung explants from the effects of LPS. Activating NF-κB in macrophages inhibited airway branching, lead to abnormal lung morphogenesis, and induced perinatal lethality. In addition to the effects of macrophage activation on lung morphogenesis, NF-κB signaling can alter normal macrophage maturation. Flow cytometry experiments show two macrophage populations in the fetal lung, CD11bhiF4/80lo and CD11bloF4/80hi, with most macrophages being CD11bhiF4/80lo. After NF-κB activation, there is an increase in the CD11bhiF4/80lo subpopulation, which expressed higher levels of CD204 and CD206. High levels of CD204 and CD206 are also found on mature, alveolar macrophages, indicating similarities in marker expression with the CD11bloF4/80hi subpopulation. Fetal lung macrophages are unique in that they do not follow the typical polarization paradigm, but rather a maturation pathway towards alveolar macrophages. Overall, macrophages have a primary role in the fetal lung inflammatory. NF-κB activation in macrophages inhibits lung development and influences fetal macrophage maturation.

Previous research in cross-language speech perception has shown that English-learning infants at 6--8 months of age and younger can discriminate both native and non-native consonant contrasts. However, by 10--12 months of age, infants' discrimination performance becomes more like that of adults in that they show difficulty discriminating non-native, but not native phonetic contrasts. In the present study, infants (6- to 8- and 10- to 12-months-old) and adults from two language environments (French and English) were compared on their perception of two English stop-fricative contrasts, /b - v/ and /d - th /. The present findings show trends that replicate patterns of results observed in previous developmental cross-language studies, supporting the conclusion that phonetic perception shifts from a language-general to a language-specific direction within the first year of life. The findings illustrate the benefits of conducting direct language comparisons and using similar test procedures across different age groups when studying speech perception development.

The language and communication abilities of a deaf child (15;9) acquiring American Sign Language (ASL) as his first-language after puberty were investigated. The participant had been exposed to ASL for approximately three years at the time of testing. Background information and data concerning the participant's language and communication skills were collected from his foster parents. Videotaped language samples were collected in conversational and narrative contexts using various elicitation devices. Data from the language samples were transcribed and analyzed with respect to the participant's lexical, morphological, syntactic, and pragmatic skills. Comparison of the results of these analyses to what is known about native language acquisition, homesign, and late first-language acquisition revealed both similarities and differences between the participant and members of each of these three groups. Contrary to previous claims of dissociations between lexical, morphological, syntactic, and pragmatic development by late first-language learners, the participant demonstrated relatively similar abilities across different areas of language and communication. The theoretical implications of these results, as well as clinical implications and directions for future research, are discussed.

In this dissertation, the phonetic production and perception abilities of simultaneous bilinguals exposed to both Canadian English (CE) and French (CF) from birth were tested to determine whether their abilities in the two languages are best described as autonomous or interdependent. For this purpose, the similarities and differences in production and perception of coronal stops, /d/ and /t/, in CE and CF by monolinguals and simultaneous bilinguals were investigated in three studies. / Coronal stops in CE and CF are thought to differ subtly in place of articulation; CE coronal stops are transcribed as having an alveolar place of articulation whereas CF coronal stops are transcribed as having a dental place of articulation. In Study 1, the acoustics of coronal stops produced in isolated words in CE and CF by monolingual CE and CF speakers were analysed. Because there were no previous reports of acoustic characteristics of coronal stops in CE and CF, data from this study provide the foundation for comparisons of monolinguals and bilinguals in Studies 2 and 3. Results from Study 1 established that bursts associated with CE and CF stops differ in relative burst intensity and in burst spectral measures. / In Study 2, acoustics of coronal stops embedded in sentences in CE and CF produced by simultaneous bilinguals and monolinguals was compared. Results indicated that production of CE and CF coronal stops by simultaneous bilinguals and monolinguals differs in that simultaneous bilinguals only used a subset of cues observed in cross-language comparison of monolingual productions. / Finally, in Study 3, the discrimination of /dV/ syllables in CE and CF was compared across simultaneous bilinguals, monolingual CE speakers, monolingual CF speakers and early L2 learners of French. The simultaneous bilinguals were significantly better than monolingual CF speakers and early L2 learners of French. They were also better than the monolingual CE speakers, but only on one out of the two vowel contexts on which they were tested. Although there are similarities in the production and perception abilities of simultaneous bilinguals and monolingual speakers, the differences between them support an interdependent relationship between the two languages of bilinguals.

In recent times, major advances have been made towards understanding sexual dimorphism in the brain on a molecular basis. This thesis summarises my modest contributions to these endeavours. Sexual dimorphisms are manifested throughout the spectrum of biological complexity, and can be studied by numerous approaches. The approach of this thesis is to explore sex-biased gene expression in mammalian somatic tissues. Paper I describes an evolutionarily conserved sexual gene expression pattern in the primate brain. Conserved sex-biased genes may underlie important sex differences in neurobiology. In Paper II, Y-chromosome genes expressed across several regions of the human male brain during mid-gestation are identified. Such genes may play male-specific roles during brain development. The studies of Papers III and IV explore sex-biased gene expression in several somatic tissues from mouse. The amount of genes with sex-biased expression varied in different brain regions. The striatum was particularly interesting, with an order of magnitude increase in the number of sex-biased genes as compared to the other included brain regions. Of potentially wider significance are my observations regarding the transcriptional regulation of domains that escape X-chromosome inactivation (XCI). Specifically, I provide the first evidence that long non-coding RNAs (lncRNAs) transcribe together with protein-coding genes in XCI-escaping domains. This raises the possibility that lncRNAs mediate the transcriptional regulation of XCI-escaping domains. I also present evidence that the mouse X-chromosome has undergone both feminisation and de-masculinisation during evolution, as indicated by the sex-skewed regulation of genes on this chromosome. This finding is relevant for understanding the selective forces that shaped the mammalian X-chromosome. In the final chapter, Paper V, the generation of a novel transgenic mouse line, Gpr101-Cre, is described. Its progeny can be used for functional studies of striatum, a brain structure with major sexual dimorphism, as is further demonstrated in the Papers of this thesis.

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Adult neurogenesis is defined as the generation of new nerve cells in the adult central nervous system (CNS). Stimulating neurogenesis may potentially offer a therapeutic approach for neurodegenerative diseases such as Parkinson???s disease. However, it is not clear why neurogenesis does not normally replace neurons lost in these diseases. As a first step to address this problem it is necessary to identify mechanisms that regulate adult neurogenesis in the normal and diseased brain and further, determine if manipulating these mechanisms may offer therapeutic potential. In this thesis, we identify activin A, a member of the transforming growth factor ?? (TGF??) superfamily, as a significant regulator of neurogenesis. We demonstrate that mRNA encoding activin A is expressed after a KA injury, and that inhibition of this activin A profoundly impairs neurogenesis in the hippocampus. Further we demonstrate that activin A impairs gliosis and also has potent anti-inflammatory effects in the injured hippocampus. Finally, we provide evidence that the majority of activin A???s neurogenic effect results from its potent anti-inflammatory actions. Our study draws a clear link between neurogenesis and inflammation in the CNS and is the first to provide evidence that this process is regulated through activin signalling. Since inflammation is now believed to be an important component of many neurological diseases we suggest that therapeutic compounds that enhance activin A signalling may offer a therapeutic approach for treating these diseases by suppressing inflammation and stimulating neurogenesis.

This thesis proposes a theory for fundamental aspects of the evolution and development of the representational mind. Building on Perner's (1991) theory of representational development, it is suggested that mind evolved from the ability to represent current reality (primary mind) to further entertain secondary representations of hypothetical content (collating mind) to finally represent representational relations themselves (metamind). In child development these transitions can be observed by about 18 months and by about 42 to 48 months. In comparative analysis only the great apes show signs of a collating mind. Young children and great apes can, for example, pretend, consider a limited future and past, solve problems by insight, and consider others' basic mental states. By about age four children begin to show evidence for metarepresentation in their ability to pass theory-of-mind tasks. At about the same age they also gain considerable executive control which, together with metarepresentation, is the key cognitive advance of metamind. Empirical evidence suggests that various skills co-develop with metamind and the thesis includes four studies that investigate such associations. It was found that gestural representation with imaginary objects and the generation of creative problem solutions were robustly correlated with theory-of-mind measures. These results substantiate the claim for a domain-general change in cognitive ability by about age four. Understanding delayed video feedback, however, was not found to correlate with such measures and it is questioned whether delayed feedback tasks measure an extended sense of self as has been proposed (Povinelli, 1995; Suddendorf & Corballis, 1997). Great apes, while showing evidence for a collating mind, have not yet provided any convincing evidence for metamind. It is thus suggested that metamind developed after the split from the line that led to modern chimpanzees about five million years ago. Metamind, it is argued, was a prime mover in human phylogeny and is a crucial step in human ontogeny. / Subscription resource available via Digital Dissertations only.