Endothelin 3 induces skin pigmentation in a keratin-driven inducible mouse model

Endothelin 3 (Edn3) is a ligand important to developing neural crest cells (NCC). Some NCC eventually migrate into the skin and give rise to the pigment-forming melanocytes found in hair follicles. Edn3's effects on NCC have been largely explored through spontaneous mutants and cell culture experiments. These studies have shown the Endothelin receptor B/Edn3 signaling pathway to be important in the proliferation/survival and differentiation of developing melanocytes. To supplement these investigations I have created doxycycline-responsive transgenic mice which conditionally over-express Edn3. These mice will help us clarify Edn3's role during the development of early embryonic melanoblasts, differentiating melanocyte precursors in the skin, and fully differentiated melanocytes in the hair follicle. The transgene mediated expression of Edn3 was predominantly confined to the roof plate of the neural tube and surface ectoderm in embryos and postnatally in the epidermal keratinocytes of the skin. Relative to littermate controls, transgenics develop increased pigmentation on most areas of the skin. My doxycycline-based temporal studies have shown that both embryonic and postnatal events are important for establishing and maintaining pigmented skin. The study of my Edn3 transgenic mice may offer some insight into the genetics behind benign dermal pigmentation and offer clues about the time periods important in establishing these conditions. This apparently abnormal development is echoed in a benign condition of human skin. Cases of dermal melanocytosis, such as common freckles, Mongolian spotting, and nevus of Ito demonstrate histological and etiological characteristics similar to those of the transgenic mice generated in this study.

Three empirical essays on startups' survival using the Kauffman Firm Survey

This dissertation studies newly founded U.S. firms' survival using three different releases of the Kauffman Firm Survey. I study firms' survival from a different perspective in each chapter. ^ The first essay studies firms' survival through an analysis of their initial state at startup and the current state of the firms as they gain maturity. The probability of survival is determined using three probit models, using both firm-specific variables and an industry scale variable to control for the environment of operation. The firm's specific variables include size, experience and leverage as a debt-to-value ratio. The results indicate that size and relevant experience are both positive predictors for the initial and current states. Debt appears to be a predictor of exit if not justified wisely by acquiring assets. As suggested previously in the literature, entering a smaller-scale industry is a positive predictor of survival from birth. Finally, a smaller-scale industry diminishes the negative effects of debt. ^ The second essay makes use of a hazard model to confirm that new service-providing (SP) firms are more likely to survive than new product providers (PPs). I investigate the possible explanations for the higher survival rate of SPs using a Cox proportional hazard model. I examine six hypotheses (variations in capital per worker, expenses per worker, owners' experience, industry wages, assets and size), none of which appear to explain why SPs are more likely than PPs to survive. Two other possibilities are discussed: tax evasion and human/social relations, but these could not be tested due to lack of data. ^ The third essay investigates women-owned firms' higher failure rates using a Cox proportional hazard on two models. I make use of a never-before used variable that proxies for owners' confidence. This variable represents the owners' self-evaluated competitive advantage. ^ The first empirical model allows me to compare women's and men's hazard rates for each variable. In the second model I successively add the variables that could potentially explain why women have a higher failure rate. Unfortunately, I am not able to fully explain the gender effect on the firms' survival. Nonetheless, the second empirical approach allows me to confirm that social and psychological differences among genders are important in explaining the higher likelihood to fail in women-owned firms.^

Evaluating Effects of Everglades Restoration on American Crocodile Populations in South Florida Using a Spatially-Explicit, Stage-Based Population Model

The distribution and abundance of the American crocodile (Crocodylus acutus) in the Florida Everglades is dependent on the timing, amount, and location of freshwater flow. One of the goals of the Comprehensive Everglades Restoration Plan (CERP) is to restore historic freshwater flows to American crocodile habitat throughout the Everglades. To predict the impacts on the crocodile population from planned restoration activities, we created a stage-based spatially explicit crocodile population model that incorporated regional hydrology models and American crocodile research and monitoring data. Growth and survival were influenced by salinity, water depth, and density-dependent interactions. A stage-structured spatial model was used with discrete spatial convolution to direct crocodiles toward attractive sources where conditions were favorable. The model predicted that CERP would have both positive and negative impacts on American crocodile growth, survival, and distribution. Overall, crocodile populations across south Florida were predicted to decrease approximately 3 % with the implementation of CERP compared to future conditions without restoration, but local increases up to 30 % occurred in the Joe Bay area near Taylor Slough, and local decreases up to 30 % occurred in the vicinity of Buttonwood Canal due to changes in salinity and freshwater flows.

UV-induced melanoma mouse model dependent on endothelin 3 over-expression

Melanoma is one of the most aggressive types of cancer. It originates from the transformation of melanocytes present in the epidermal/dermal junction of the human skin. It is commonly accepted that melanomagenesis is influenced by the interaction of environmental factors, genetic factors, as well as tumor-host interactions. DNA photoproducts induced by UV radiation are, in normal cells, repaired by the nucleotide excision repair (NER) pathway. The prominent role of NER in cancer resistance is well exemplified by patients with Xeroderma Pigmentosum (XP). This disease results from mutations in the components of the NER pathway, such as XPA and XPC proteins. In humans, NER pathway disruption leads to the development of skin cancers, including melanoma. Similar to humans afflicted with XP, Xpa and Xpc deficient mice show high sensibility to UV light, leading to skin cancer development, except melanoma. The Endothelin 3 (Edn3) signaling pathway is essential for proliferation, survival and migration of melanocyte precursor cells. Excessive production of Edn3 leads to the accumulation of large numbers of melanocytes in the mouse skin, where they are not normally found. In humans, Edn3 signaling pathway has also been implicated in melanoma progression and its metastatic potential. The goal of this study was the development of the first UV-induced melanoma mouse model dependent on the over-expression of Edn3 in the skin. The UV-induced melanoma mouse model reported here is distinguishable from all previous published models by two features: melanocytes are not transformed a priori and melanomagenesis arises only upon neonatal UV exposure. In this model, melanomagenesis depends on the presence of Edn3 in the skin. Disruption of the NER pathway due to the lack of Xpa or Xpc proteins was not essential for melanomagenesis; however, it enhanced melanoma penetrance and decreased melanoma latency after one single neonatal erythemal UV dose. Exposure to a second dose of UV at six weeks of age did not change time of appearance or penetrance of melanomas in this mouse model. Thus, a combination of neonatal UV exposure with excessive Edn3 in the tumor microenvironment is sufficient for melanomagenesis in mice; furthermore, NER deficiency exacerbates this process.^

UV-Induced Melanoma Mouse Model Dependent on Endothelin 3 Over-Expression

Melanoma is one of the most aggressive types of cancer. It originates from the transformation of melanocytes present in the epidermal/dermal junction of the human skin. It is commonly accepted that melanomagenesis is influenced by the interaction of environmental factors, genetic factors, as well as tumor-host interactions. DNA photoproducts induced by UV radiation are, in normal cells, repaired by the nucleotide excision repair (NER) pathway. The prominent role of NER in cancer resistance is well exemplified by patients with Xeroderma Pigmentosum (XP). This disease results from mutations in the components of the NER pathway, such as XPA and XPC proteins. In humans, NER pathway disruption leads to the development of skin cancers, including melanoma. Similar to humans afflicted with XP, Xpa and Xpc deficient mice show high sensibility to UV light, leading to skin cancer development, except melanoma. The Endothelin 3 (Edn3) signaling pathway is essential for proliferation, survival and migration of melanocyte precursor cells. Excessive production of Edn3 leads to the accumulation of large numbers of melanocytes in the mouse skin, where they are not normally found. In humans, Edn3 signaling pathway has also been implicated in melanoma progression and its metastatic potential. The goal of this study was the development of the first UV-induced melanoma mouse model dependent on the over-expression of Edn3 in the skin. The UV-induced melanoma mouse model reported here is distinguishable from all previous published models by two features: melanocytes are not transformed a priori and melanomagenesis arises only upon neonatal UV exposure. In this model, melanomagenesis depends on the presence of Edn3 in the skin. Disruption of the NER pathway due to the lack of Xpa or Xpc proteins was not essential for melanomagenesis; however, it enhanced melanoma penetrance and decreased melanoma latency after one single neonatal erythemal UV dose. Exposure to a second dose of UV at six weeks of age did not change time of appearance or penetrance of melanomas in this mouse model. Thus, a combination of neonatal UV exposure with excessive Edn3 in the tumor microenvironment is sufficient for melanomagenesis in mice; furthermore, NER deficiency exacerbates this process.