Thesis (Ph. D.)--University of Missouri-Columbia, 2004. / Typescript. Vita. Includes bibliographical references (leaves 179-221). Also available on the Internet.

Thesis (Ph. D.)--University of Missouri-Columbia, 2004. / Typescript. Vita. Includes bibliographical references (leaves 179-221). Also available on the Internet.

Thesis (Ph. D.)--University of Washington, 1996. / Vita. Includes bibliographical references (leaves [145]-157).

Thesis (doctoral)--Nijmegen, 1980.

Source: Dissertation Abstracts International, Volume: 70-07, Section: B, page: 4057. Adviser: Elaine Symanski. Includes bibliographical references.

Thesis (Ph. D.)--Brigham Young University. Dept. of Physiology and Developmental Biology, 2006. / Includes bibliographical references (p. 108-115).

The transcription factor DEAF-1 is the mammalian homologue of a critical Drosophila developmental gene and is essential for neonatal survival in mice. Haploinsufficiency of Deaf-1 in the testis of adult mice was initially thought to cause loss of spermatogenesis and disrupted morphology of the seminiferous tubules, and this heterozygosity was thought to be sufficient to disrupt epigenetic programming in the developing sperm to produce inheritance of testicular defects in both heterozygous and genotypically normal offspring. Although Deaf-1 knockout mice do display disrupted testis structure, infertility at advanced age, hyperproliferation of early germ cells, and abnormal staging of seminiferous tubules, this phenotype was also observed in normal mouse strains that were born in the SIUC vivarium. Mice ordered from a vendor and raised at SIUC did not show testicular defects. This suggests an environmental factor at the SIUC vivarium may act as an endocrine disruptor during embryonic testicular development. Deaf-1-/- mice die soon after birth, often as the result of exencephaly, a gross neural tube defect (NTD). Unlike many mouse models, exencephalic Deaf-1-/- mice do not display a higher incidence of NTDs in females as compared to their male littermates. DEAF-1 promotes Bax-mediated apoptosis; studies using terminal UTP nick-end labeling (TUNEL) suggest a global increase in apoptosis in both exencephalic and normal Deaf-1-/- fetuses during neurulation as compared to their Deaf-1+/+ littermates. This indicates that Deaf-1 is crucial for correct apoptotic patterning during development, which, in turn, is essential for neural tube closure. Finally, cDNA microarray comparison of e14.5 Deaf-1 knockout and wildtype fetuses reveals expression of translation initiation factor 4g3 (Eif4g3) to be downregulated in Deaf-1-/- fetuses. Electrophoretic mobility shift assay using recombinant DEAF-1, and chromatin immunoprecipitation assay of a human cell line confirmed DEAF-1 could bind the eIF4G3 promoter both in vitro and in vivo. Additionally, transcription of the Deaf-1 Antisense Transcript (Das) was found to be significantly downregulated in both e14.5 fetuses and e18.5 fetal brains from Deaf-1-/- mice, suggesting that either lack of Deaf-1 protein or lack of exons 2 through 5 in Deaf-1 knockout mice causes changes in levels of the noncoding RNA that shares Deaf-1's promoter in the mouse.

With a birth prevalence of 1 in 1000, neural tube defects (NTD)s contribute considerably to morbidity and healthcare costs. Known genetic and environmental (non-inherited) risk factors for NTDs account for a small portion of risk, suggesting unidentified risk factors. In animal studies, maternal alcohol and pesticide exposures, independently, led to excess neural cell death, resulting in too few cells for neural tube closure. Human studies report no association between alcohol exposure and NTDs, but small to moderate positive associations for pesticide exposure. Such human etiologic studies of NTDs require a large base population, but frequently include only live births. Exclusion of cases by pregnancy outcomes may create ascertainment and response bias, complicating interpretation of findings. Using data from the National Birth Defects Prevention Study (NBDPS) and the Iowa Registry for Congenital and Inherited Disorders (IRCID), the independent effects of maternal periconceptional (1 month prior through 2 months postconception) alcohol and occupational pesticide exposure on the development of NTDs were examined, and differences in Iowa NTD cases were characterized by pregnancy outcome. Maternal reports of alcohol exposure were obtained for 1223 NTD case infants and 6807 control infants. Adjusted odds ratios, estimated using multivariate logistic regression, were near unity for NTDs by any maternal alcohol exposure, binge episode(s), and type(s) of alcohol consumed. Occupational pesticide exposure was assigned by industrial hygienists for mothers of 502 case and 2950 control infants. Adjusted odds ratios for any exposure and cumulative exposure to any pesticide, insecticides only, and insecticides + herbicides + fungicides were near unity for NTDs. Insecticide + herbicide exposure was positively associated with spina bifida. Among the 279 Iowa NTD case infants ascertained by the IRCID, 167 live births and 112 were other pregnancy outcomes (fetal deaths and elective terminations), which increased in proportion over time. Selected infant and maternal characteristics of live births and other pregnancy outcomes were similar. NBDPS eligibility varied significantly by pregnancy outcome, but participation rates did not. NTD case mothers were similar to Iowa NBDPS control mothers. Efforts were made to improve upon prior etiologic studies of these exposures and NTDs, including increased sample size and improved exposure specificity. Some exposure strata (e.g., herbicides only) and outcome strata (e.g., other rare subtypes) were limited by small numbers. All results may have been affected by response and ascertainment bias. Future studies should aim to use similarly detailed exposure classification methods, increase sample size in less prevalent NTD subtypes, and improve ascertainment of fetal deaths.

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