Yes-associated protein 65 (YAP) contains multiple protein-protein interaction domains and functions as both a transcriptional co-activator and as a scaffolding protein within the cytoplasm or nucleus. Given that YAP binds to so many proteins that are critical for proper embryonic development and that this factor functions as a transcriptional co-activator, YAP likely plays an important role during early embryonic development.
Given that YAP knockout mice struggled to progress normally through early development, in part because of nutritional deficiencies, we sought to better characterize a role for YAP during this time period by using embryos that develop externally: Xenopus laevis and Danio rerio. YAP morpholino (MO)-mediated loss-of-function resulted in a delay of mesoderm induction and severely impaired A-P axis elongation, phenotypes that were similar to YAP-/- mice. YAP gain-of-function experiments in Xenopus laevis expanded the progenitor populations in the neural plate and neural plate border zone, while concomitantly inhibiting differentiation markers for the neural crest, preplacodal ectoderm, hatching gland, epidermis, and somitic muscle.
Regulation of gene expression is critically important in development and improper regulation of gene expression can lead to a variety of developmental defects, such as loss of conceptus, birth defects, and cancer. I found that yap expression is controlled by a TATA-less promoter, which includes a GC box where Sp1 binds and regulates yap transcription. I also found that adrenomedullin, a multifunctional peptide hormone known to act as a vasodilator, angiogenic factor, regulator of placental development, and tumor growth promoter, is a newly identified, putative target of YAP.
These studies demonstrate that YAP is involved in the process of cell differentiation and the lack or overabundance of YAP protein disrupts the developmental time line of vertebrates with grievous consequences. Understanding the mechanistic details of these effects involve delineating the transcriptional control of YAP and its target genes. In the future, elucidating the linkage between YAP, the nuclear architecture, and transcriptional regulation will bolster our understanding of cell differentiation.
|Advisor:||Milgram, Sharon L.|
|Commitee:||Bankaitis, Vytas A., Brennwald, Patrick J., Moody, Sally A.|
|School:||The University of North Carolina at Chapel Hill|
|Department:||Cell & Developmental Biology|
|School Location:||United States -- North Carolina|
|Source:||DAI-B 72/10, Dissertation Abstracts International|
|Subjects:||Cellular biology, Developmental biology|
|Keywords:||Cell differentiation, Embryonic development, Hippo signaling, Yes-associated protein|
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