Elucidating the Role of Cellular Architecture in the Developing Pancreas

dc.contributor.advisorMacDonald, Raymond J.en
dc.contributor.committeeMemberJohnson, Jane E.en
dc.contributor.committeeMemberCarroll, Thomas J.en
dc.contributor.committeeMemberCleaver, Ondineen
dc.creatorMarty Santos, Leilani Marieen
dc.creator.orcid0000-0002-0515-4258
dc.date.accessioned2018-01-04T21:10:47Z
dc.date.available2018-01-04T21:10:47Z
dc.date.created2015-12
dc.date.issued2015-11-30
dc.date.submittedDecember 2015
dc.date.updated2018-01-04T21:04:12Z
dc.description.abstractMany studies have focused on examining the intrinsic factors such as transcriptional regulators that instruct the step-wise acquisition of β-cell fate in the developing pancreas, with the intention of recapitulating the events necessary in order to generate these cells in vitro for replacement therapies. Directed differentiation protocols have improved upon transitioning from 2D to 3D cultures, indicating that the 3D microenvironment in which β cells are born is critical for the acquisition of their cell fate. However, little is known about the mechanisms through which the 3D architecture of the developing pancreas mediates cell fate specification and epithelial organization. In order to address some of the remaining gaps in the field, we proceeded to characterize the Pdx1-/- embryo, a mutant in which pancreatic cell fate and architecture had been reported to fail early in its development, to determine whether the developmental failure was related to defects in the epithelial architecture. After elucidating that Pdx1 is a transcriptional regulator of the cellular adhesion molecule E-cadherin, we then examined the effect that tissue-specific deletion of this molecule has on the developing pancreas. We determined that E-cadherin regulates both endocrine cell fate and isletogenesis, as we observe that there is a reduction in endocrine progenitors and total endocrine volume, in addition to a failure of the endocrine cells to coalesce into islets. Our findings also demonstrate that acinar cells are lost in the post-natal E-cadherinf/f;Pdx1Cre pancreas, due to an increase in cell death, suggesting that E-cadherin is capable of regulating cell survival. This body of work indicates that architectural molecules play a critical role in the regulation of cell fate specification and epithelial morphogenesis in the developing pancreas.en
dc.format.mimetypeapplication/pdfen
dc.identifier.oclc1017760181
dc.identifier.urihttps://hdl.handle.net/2152.5/4454
dc.language.isoenen
dc.subjectCadherinsen
dc.subjectCell Differentiationen
dc.subjectHomeodomain Proteinsen
dc.subjectPancreasen
dc.subjectTrans-Activatorsen
dc.titleElucidating the Role of Cellular Architecture in the Developing Pancreasen
dc.typeThesisen
dc.type.materialtexten
thesis.degree.departmentGraduate School of Biomedical Sciencesen
thesis.degree.disciplineGenetics and Developmenten
thesis.degree.grantorUT Southwestern Medical Centeren
thesis.degree.levelDoctoralen
thesis.degree.nameDoctor of Philosophyen

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