The long-term goal of this work is to develop a mechanistic understanding of the development of the neural crest, a stem cell like progenitor population central to the evolution of the vertebrates, as well as to understand how congenital malformations and diseases such as cancer result from the aberrant development of this cell type. We seek to understand at a mechanistic and biochemical level how the stem cell population is formed, what controls the maintenance of its multipotency, how the migratory and invasive behavior of these cells is regulated, and ultimately, how individual neural crest cells are directed to adopt specific derivative fates. The overall goal of this proposal is to identify novel components and interactions within the NC-GRN. More specifically it seeks to, using next generation sequencing, identify miRNAs required for neural crest and downstream targets of the key neural crest transcription factor Snail. We hypothesize that miRNAs play an essential role in regulating neural crest development, including its ability to give rise to the craniofacial skeleton. The identity of the miRNAs expressed during neural crest development and their roles in this tissue remain largely unknown. Of the core components of the NC-GRN the Snail family of transcription factors is known to play reiterative roles during neural crest development in other model organisms. This proposal will therefore also determine what miRNAS are expressed in or excluded from neural crest cells as a consequence of Snail function by generating a genetic tool for ablating Snail function in a temporally controlled manner. This tool will also be used to identify, on a genome wide scale, Snail transcriptional targets during key stages of neural crest development. This work is of high significance for understanding the normal development of neural crest cells and neural crest derivatives, including the craniofacial skeleton, and for understanding a broad range of neural crest linked congenital defects.
Neural crest (NC) cells make extensive contributions to craniofacial structures and are of central importance to understanding many congenital disorders. Our studies will provide essential insights into the regulation of proteins playing central roles in both NC development and disease processes.