Date of Degree
PhD (Doctor of Philosophy)
Robert A. Cornell
Neural crest is a vertebrate-specific population of embryonic precursor cells thought to have been essential in vertebrate evolution. During development, a group of naïve ectoderm cells are induced to become neural crest and then undergo series of developmental events to give rise to diverse derivatives. Failure of these events often leads to malfunction of neural crest derived tissues and organs. This thesis focuses on the genetic regulation of two events during neural crest development, induction and differentiation.
Neural crest induction refers to the specification of ectoderm cells to the neural crest lineage. It is believed that combinatorial activity of transcription factors governs neural crest induction, but the function of specific transcription factors in this process are not yet clear. The AP-2 family of transcription factors is implicated in control of neural crest development, but whether there is a cell autonomous role of AP-2 transcription factors in neural crest induction has remained uncertain. Here I show that in zebrafish, two AP-2 family members, Tfap2a and Tfap2c, are required redundantly for neural crest induction, and that this requirement is cell autonomous. Failure of neural crest induction in the zebrafish embryos that are devoid of Tfap2a and Tfap2c is not caused by defects in cell survival or cell proliferation, but rather appears to result from a failure neural crest cell fate specification. Simultaneous knockdown of Tfap2a and Tfap2c is one of the only known genetic manipulations that result in failure of neural crest induction. Thus the Tfap2a/c double knockdown embryos will be useful for further studies on the emergence of neural crest during both development and evolution.
The second section of my thesis concerns differentiation of neural crest derived zebrafish melanophores. This study reveals that Tfap2a and another AP-2 family member, Tfap2e, redundantly and autonomously regulate melanophore differentiation. This is the first report on the function of Tfap2e in any animal. Given that the expression of AP-2 transcription factors is tightly associated with the metastasis potential of human melanoma, my study reinforces the view that cancer cells co-opt regulatory pathways employed in embryonic development.
Copyright 2008 Wei Li