Genetics and Genomics Commons^™

Genetic Regulation Of Müllerian Duct Regression, Malcolm Moses

Dissertations & Theses (Open Access)

Mammals, including humans, develop progenitor tissues for both male and female reproductive tract organs before they fully differentiate into a male or female tract. The progenitor tissue for the male reproductive tract is known as the Wolffian duct (WD), and the progenitor tissue for the female reproductive tract is the Müllerian duct (MD). The WD further differentiates into the vas deferens, epididymis, and seminal vesicle, while the MD differentiates into the oviduct, uterus and upper vagina. An essential step in sex differentiation for males is the regression of the MD. This regression initiates with anti-Müllerian hormone (Amh) transcription …

Genetic Pathway Analysis Of Abnormal Facial Development In Nonsyndromic Cleft Lip And Palate, Lorena Maili

Dissertations & Theses (Open Access)

Nonsyndromic cleft lip with or without cleft palate (NSCLP) is the most common craniofacial birth defect resulting from incomplete fusion of the facial prominences during development, which leaves a gap in the lip, primary palate and/or the secondary palate. NSCLP affects 135,000 NSCLP newborns worldwide each year based on a birth prevalence of 1 per 700 live births. While surgical treatments have dramatically improved, many long-term health issues persist, imposing significant medical, psychosocial and economic burdens. Familial aggregation and segregation analyses suggest genetic contributions underlie NSCLP, but despite decades of study, only a small portion of the NSCLP genetic liability …

The Genome-Wide Roles Of The Lung Lineage Transcription Factor Nkx2-1 In The Regulation Of Opposing Cell Fates In Vivo, Danielle Renae Little

Dissertations & Theses (Open Access)

Lineage transcription factors mark, promote, and maintain multiple distinct cell types originating from a common progenitor. Despite their essential role, how such factors function and bind genome wide to orchestrate the epigenetic changes necessary to form and maintain these identities in vivo is unclear. One lineage transcription factor NK Homeobox 2-1 (NKX2-1) is expressed throughout the lung epithelium during development and was thought to be lost in the extraordinarily thin cell type required for gas exchange– the alveolar type 1 (AT1) cell. Complementing precise genetic knockouts with cell type-specific ChIP-seq, ATAC-seq, and scRNA-seq, our study shows that AT1 and AT2 …

Artificial Intron Technology To Generate Conditional Knock-Out Mice, Amber N. Thomas-Gordon

Dissertations & Theses (Open Access)

Genetic engineering has been re-shaped by the invention of new tools in modern biotechnology in a way that offers precision and efficiency in modifying the genome at a single nucleotide level and/or allowing precise control of gene expression. Such gene manipulation brings about significant findings and revelations in comprehending more about embryonic development, cellular and physiological functions, and disease pathology. Current methods used to produce conditional knockouts have limitations on conditional allele placement and modification varies among genes in different organisms. Thus, a system for generating conditional alleles with fidelity remains a challenge. My goal was to examine an approach …

Platiscity Of C. Elegans Germline Stem Cells Under Nutritional And Metabolic Stress, Kenneth Trimmer

Dissertations & Theses (Open Access)

Stem cells are integral for tissue maintenance and fertility. Therefore, understanding how stem cells are regulated under stress is imperative. When confronted with acute starvation, stem cells must conserve energy and metabolites to cope with the lack of an external source. Caenorhabditis elegans germline stem cells (GSCs) are an excellent model for studying stem cell properties and regulation as they can divide throughout the life of the organism. While GSCs are an adult stem cell population, their cell cycle structure more closely mimics mouse and human embryonic stem cells with short G1 and long S phases. In this thesis, I …

Phosphorylation Impairs Dicer1 Function To Accelerate Aging And Tumorigenesis In Vivo, Neeraj Aryal

Dissertations & Theses (Open Access)

Altered DICER1 protein levels are associated with developmental disorders, infertility, macular degenerative blindness, aging, and cancer in humans. Recently, post-translational regulation of Dicer1 via phosphorylation has been described in C. elegans. Oscillation of Dicer1 phosphorylation to regulate its activity is essential for germ cell development and embryogenesis in worms. These observations led us to posit that Dicer1 protein levels and activity are under tight regulation for normal mammalian homeostasis. To test whether phosphorylation of Dicer1 regulates its activity in mammals, I generated phospho-mimetic knock-in mouse models by replacing Serines 1712 and 1836 with Aspartic acids individually or together (dual …

Impact Of Differentiation Status Of Kidney Progenitors In Wilms Tumor Development, Le Huang

Dissertations & Theses (Open Access)

Wilms tumor is one of the most common solid tumors in children. It is an embryonic cancer of the kidney and is thought to arise from undifferentiated renal mesenchyme. However, the differentiation status of cells in the mesenchyme that can give rise to Wilms tumors is unknown. Gene expression analysis of a large panel of Wilms tumor patients has identified different subsets of Wilms tumors that are distinct in their clinical outcomes and gene expression signatures. These subsets express specific genes that correspond to different stages of differentiation during renal development, suggesting that Wilms tumors may arise from transformed cells …

Elucidating The Role Of Rumi And O-Glucosylation In The Drosophila Eye, Amanda Haltom

Dissertations & Theses (Open Access)

Rumi is a protein O-glucosyltransferase that adds the sugar O-glucose onto the serine in the target sequence C-S-X-S-(P/A)-C found within properly folded EGF repeats. It was first discovered to modify the Drosophila Notch extracellular domain and to be required for Notch signaling in a temperature dependent manner, but other targets of Rumi remained unknown. Several other proteins in the Drosophila proteome harbor multiple consensus sequence highly predictive of O-glucose, including the transmembrane protein Crumbs and the secreted protein Eyes shut (Eys). Both of these proteins are required for proper eye development and mutations in their human homologs …

P53 Maintains Hepatic Cell Identity During Liver Regeneration, Zeynep Hande Coban Akdemir

Dissertations & Theses (Open Access)

p53 MAINTAINS HEPATIC CELL IDENTITY DURING LIVER REGENERATION

Zeynep Hande Coban Akdemir, B.S.,M.A.

Advisory Professor: Michelle Craig Barton, Ph.D.

p53 is a tumor suppressor that has been well studied in tumor-derived, cultured cells. However, its functions in normal proliferating cells and tissues are generally overlooked. We propose that p53 functions during the G1-S transition can be studied in normal, differentiated cells during surgery-induced liver regeneration. Two-thirds partial hepatectomy (PH) of mouse liver offers a unique model to compare p53 functions in regenerating versus sham (control) cells. My hypothesis is that intersection of global expression analyses (microarray and RNA sequencing) and …

Characterization Of Ftsa-Ftsn Interaction During Escherichia Coli Cell Division, Kimberly.Busiek@Gmail.Com K. Busiek

Dissertations & Theses (Open Access)

Division of a bacterial cell into two equal daughter cells requires precise assembly and constriction of the division machinery, or divisome. The Escherichia coli divisome includes nearly a dozen essential cell division proteins that assemble at midcell between segregating sister chromosomes. FtsZ, a homolog of eukaryotic tubulin, is the first essential cell division protein to localize at midcell where it polymerizes into a ring-shaped scaffold (Z ring). Establishment of the Z ring is required for recruitment of downstream cell division proteins including FtsA, a cytoplasmic protein that tethers the Z ring to the inner membrane. Following localization of FtsA and …

Genetic Analysis Of The Hippo Pathway In Mouse Liver, Li Lu

Dissertations & Theses (Open Access)

Cancer therapy and tumor treatment remain unsolved puzzles. Genetic screening for tumor suppressor genes in Drosophila revealed the Hippo-signaling pathway as a kinase cascade consisting of five core components. Disrupting the pathway by deleting the main component genes breaks the balance of cell proliferation and apoptosis and results in epithelial tissue tumorigenesis. The pathway is therefore believed to be a tumor suppressor pathway. However, a corresponding role in mammals is yet to be determined. Our lab began to investigate the tumor suppression function of the potent mammalian Hippo pathway by putting floxed alleles into the mouse genome flanking the functional-domain-expressing …

Cell Polarity Regulates Organ Growth Through The Hippo Pathway, Chiao-Lin Chen

Dissertations & Theses (Open Access)

Defects in apical-basal cell polarity and abnormal expression of cell polarity determinants are linked to human cancer. Loss of polarity is highly correlated with malignancy. In Drosophila, perturbation of apical-basal polarity, including overexpressing the apical determinant Crumbs, can lead to uncontrolled tissue growth. Cells mutant for the basolateral determinant scribble overproliferate and can form neoplastic tumors. Interestingly, scribble mutant clones that arise in wild-type tissues are eliminated and therefore do not manifest their tumorigenic potential. However, the mechanisms by which cell polarity coordinates with growth control pathways in developing organs to achieve appropriate organ size remain obscure.

To investigate …

Gene Discovery In Nonsyndromic Cleft Lip With Or Without Cleft Palate, Brett T. Chiquet

Dissertations & Theses (Open Access)

Nonsyndromic cleft lip with or without cleft palate (NSCLP), a common, complex orofacial birth defect that affects approximately 4,000 newborns each year in the United States, is caused by both genetic and environmental factors. Orofacial clefts affect the mouth and nose, causing severe deformity of the face, which require medical, dental and speech therapies. Despite having substantial genetic liability, less than 25% of the genetic contribute to NSCLP has been identified. The studies described in this thesis were performed to identify genes that contribute to NSCLP and to demonstrate the role of these genes in normal craniofacial development. Using genome …

The Role And Mechanism Of The Homeobox Gene Dlx4 In Transforming Growth Factor-B Resistance In Cancer, Bon Q. Trinh

Dissertations & Theses (Open Access)

Transforming growth factor-b (TGF-b) is a cytokine that plays essential roles in regulating embryonic development and tissue homeostasis. In normal cells, TGF-b exerts an anti-proliferative effect. TGF-b inhibits cell growth by controlling a cytostatic program that includes activation of the cyclin-dependent kinase inhibitors p15^Ink4B and p21^WAF1/Cip1 and repression of c-myc. In contrast to normal cells, many tumors are resistant to the anti-proliferative effect of TGF-b. In several types of tumors, particularly those of gastrointestinal origin, resistance to the anti-proliferative effect of TGF-b has been attributed to TGF-b receptor or Smad mutations. However, these mutations are absent from many …

Genetic Analysis Of The Function Of The Drosophila Doublesex-Related Factor Dmrt93b, Diana O'Day

Dissertations & Theses (Open Access)

DMRT (Doublesex and Mab-3 related transcription factor) proteins generally associated with sexual differentiation in many organisms share a common DNA binding domain and are often expressed in reproductive tissues. Aside from doublesex, which is a central factor in the regulation of sex determination, Drosophila possesses three different dmrt genes that are of unknown function. Because the association with sexual differentiation and reproduction is not universal and some DMRT proteins have been found to play other developmental roles we chose to further characterize one of these Drosophila genes. We carried out genetic analysis of dmrt93B, which was previously found to be …

Validation Of The Activation Of Aurora B Kinase By Caenorhabditis Elegans Tousled-Like Kinase And The Identification Of Cyclin B3 As A Phospho-Specific Tlk-1 Interactor, Gary Michael Deyter

Dissertations & Theses (Open Access)

A hallmark of tumorigenesis and certain birth defect syndromes is the loss of ploidy that can result from incorrect chromosome segregation. Chromosomes that are not partitioned properly during mitosis are often fragmented, changing the genetic makeup of daughter cells. Inheriting extrachromosomal fragments that contain cell survival genes or losing chromosomal loci that encode tumor suppressors can promote tumor development. Thus, it is essential to elucidate molecular mechanisms required for correct chromosome segregation. Chromosomes are connected to mitotic spindle microtubules by way of a proteinacous, chromosome-bound organelle called the kinetochore. Two decades of research have confirmed that the conserved Aurora B/AIR-2 …

The Consequences Of Disrupting The Mdm2-P53 Balance In Hematopoiesis, Hussein A. Abbas

Dissertations & Theses (Open Access)

The bone marrow accommodates hematopoietic stem cells and progenitors. These cells provide an indispensible resource for replenishing the blood constituents throughout an organism’s life. A tissue with such a high turn-over rate mandates intact cycling checkpoint and apoptotic pathways to avoid inappropriate cell proliferation and ultimately the development of leukemias. p53, a major tumor suppressor, is a transcription factor that regulates cell cycle, and induces apoptosis and senescence. Mice inheriting a hypomorphic p53 allele in the absence of Mdm2, a p53 inhibitor, have elevated p53 cell cycle activity and die by postnatal day 13 due to hematopoietic failure. Hematopoiesis progresses …