Tip110 is required for embryonic stem cell survival and embryonic development

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dc.contributor.advisorJohnny J. He
dc.contributor.committeeMemberGeoffrey Guttmann
dc.contributor.committeeMemberKhalid Timani
dc.creatorWhitmill, Amanda J.
dc.date.accessioned2019-08-22T21:51:03Z
dc.date.available2019-08-22T21:51:03Z
dc.date.issued2016-08-01
dc.date.submitted2017-10-13T13:06:14-07:00
dc.description.abstractHIV-1 Tat-interacting protein of 110 kDa, Tip110, has roles in tumor antigen presentation, pre-mRNA splicing, transcription of viral and host genes, and protein degradation. Tip110 is also known to be up-regulated in a variety of cancers and to regulate and/or interact with a variety of transcription factors, oncogenes, and pluripotency factors. As such, Tip110 has been shown to effect pluripotency, proliferation, apoptosis, and the cell cycle when knocked down in vitro. However, the function of Tip110 in embryonic development remains largely uncharacterized. One early study has shown that loss of a Tip110 ortholog leads to embryonic lethality in zebrafish. Our studies have shown that transgenic mouse embryos lacking expression of a functional Tip110 protein die several days post-implantation in vivo. In the present study, we determined how Tip110 knockout affects mouse embryonic development and investigated the underlying molecular mechanisms. We found that Tip110 loss did not impair embryo growth from the zygote to the blastocyst stage nor did it impair the blastocysts ability to implant into the uterine lining in vivo. Extended culture of blastocysts in vitro revealed that Tip110 loss impaired both blastocyst outgrowth formation and derivation of mouse embryonic stem cells from blastocysts. In vivo embryos could survive until the post-implantation stage where they eventually perished. The premature death of these embryos was characterized by a clear retardation in embryonic development resulting in underdeveloped or more commonly, completely resorbed mouse embryos around 8.5 or 9.5 days post coitum. Microarray analysis of Tip110-/- cells derived from mouse blastocysts revealed that Tip110 loss favored differentiation but not self-renewal, pluripotency, or cell cycling through a complex regulatory network of stem cell factors. Tip110-/- cells also had perturbations in many other signaling and cellular processes including mRNA processing and proteasome degradation. Taken together, these findings document for the first time the lethal effects of complete loss of Tip110 on mammalian embryonic development and suggest that Tip110 is an important regulator of not only embryonic development but also stem cell factors.
dc.format.mimetypeapplication/pdf
dc.identifier.urihttps://hdl.handle.net/20.500.12503/29628
dc.language.isoen
dc.provenance.legacyDownloads53
dc.subjectMedical Sciences
dc.subjectMedicine and Health Sciences
dc.subjectTip110
dc.subjectEmbryonic development
dc.subjectEmbryonic stem cells
dc.subjectSelf-renewal
dc.subjectSurvival
dc.subjectNanog
dc.subjectOct4
dc.subjectSox2
dc.titleTip110 is required for embryonic stem cell survival and embryonic development
dc.typeDissertation
dc.type.materialtext
thesis.degree.departmentGraduate School of Biomedical Sciences
thesis.degree.disciplineBiomedical Sciences
thesis.degree.grantorUniversity of North Texas Health Science Center at Fort Worth
thesis.degree.nameDoctor of Philosophy

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