Neurocristopathies are a class of syndromes that are predominately characterized by malformations in the craniofacial complex. These defects are caused by aberrant development of the neural crest (NC), a stem cell population unique to vertebrates. As a means of better understanding the molecular basis for neurocristopathies, a thorough investigation of the various aspects of NC cell development is necessary. One unique property of the NC is their broad developmental potential which grants them the ability to give rise to cell types typically attributed to multiple germ layers (mesoderm and ectoderm). Previous work from my lab has lead to the genesis of the hypothesis that the expanded embryonic potential of the NC can be attributed to the retention of stem cell-like pluripotency in these cells. Still a major unanswered question is how NC cells retain their stem cell-like potential even as neighboring cells undergo lineage restriction. Transcription factors often direct cell fate decisions or maintain cell states. In this proposal, I investigate how Sox transcription factors may regulate NC formation and their ability to maintain a stem cell-like state. SoxB1 factors, a subfamily of Sox transcription factors, are expressed in early pluripotent cells of the embryo (blastula) and help to positively regulate pluripotency in that tissue. In contrast, SoxE factors are absent from the blastula, but are robustly expressed in the NC. Effectively, there is switch in the subfamily of Sox factors that is utilized in two temporally distinct stem cell populations in the embryo. Recent work from my lab has shown that this transition from SoxB1 to SoxE factors is essential for NC formation; however, we have yet to define the mechanisms by which SoxE factors help to promote the formation of NC stem cells. In this proposal, I plan to utilize techniques such as IP-mass spectrometry and ChIP-seq to identify potential transcriptional partners and targets of Sox factors that are required for NC formation and controlling pluripotency in the blastula. Using these datasets and further experimental validation of Sox partner and target candidates, I will identify key similarities and differences between the SoxE and SoxB1 partners and targets in these stem cell populations. This will enhance our understanding of the molecular underpinnings of NC formation and maintenance of stem cell potential. Furthermore, these data will help us to understand why the formation of the NC was accompanied by a switch in the utilization of Sox factor subfamilies. !

Public Health Relevance

Neurocristopathies are a class of congenital diseases that are caused by defects in the development of an embryonic population of cells called the neural crest. In this proposal, I will investigate how Sox transcription factors regulate the formation of the neural crest. I will specifically identify Sox transcriptional partners and targets.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Postdoctoral Individual National Research Service Award (F32)
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NIDR Special Grants Review Committee (DSR)
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Frieden, Leslie A
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Northwestern University at Chicago
Schools of Arts and Sciences
United States
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