Friday, April 19, 2024
4/19/2024
The neural crest is a multipotent embryonic cell population that gives rise to most of the craniofacial skeleton, including cartilage, bone and connective tissue. Misregulation of neural crest development results in the vast majority of craniofacial malformations and birth defects. Thus, uncovering the molecular and genetic underpinnings of neural crest formation has important implications for the diagnosis and treatment of these pathologies. Neural crest development is orchestrated by a multi-level gene regulatory network, in which progenitor cells are progressively committed to a neural crest fate. This process requires not only shifts in gene expression but also an extensive remodeling of the epigenomic landscape. The chromatin remodeling events which occur between two respective stages of neural crest formation, induction and specification, are driven in part by the action of the pioneer factor TFAP2A. TFAP2A activates distinct sets of genomic regions during induction and specification of neural crest cells, and its target specificity is dependent upon its dimerization with paralogous proteins TFAP2C and TFAP2B. This heterodimeric switch between TFAP2A/C and TFAP2A/B acts to drive the transition from induction to specification, allowing for progressive cell fate commitment of neural crest cells. Consistent with this idea, TFAP2B expression is both necessary and sufficient to drive the transition from induction to specification. Analysis of an enhancer of TFAP2B has implicated SMAD2/3 nuclear effectors as predicted drivers of TFAP2B expression. This observation has led to the hypothesis that TFAP2 pioneer factors integrate environmental signals into the gene regulatory network to drive the transition from induction to specification within the neural crest lineage. The F99 phase of this proposal aims to investigate the role of SMAD nuclear effectors and their upstream signaling systems in the control of TFAP2B expression and consequently the neural crest specification program. This work will shed light on how environmental stimuli act to remodel the chromatin landscape within the presumptive neural crest. Moreover, while much focus has been paid to understand the cis-regulatory control of neural crest cell formation, we still have very little insight on the molecular mechanisms by which these cells differentiate to form the bone and cartilage of the face. Single-cell analysis of chromatin accessibility in neural crest differentiation will allow for the identification of enhancer elements specific to numerous facial compartments. Furthermore, identification of compartment-specific drivers will reveal how these regulatory factors act to orchestrate the formation of highly complex and nuanced structures within the craniofacial skeleton. Ultimately, this data may be used to gain a mechanistic understanding of the etiology of congenital birth defects linked to the misregulation of craniofacial morphogenesis.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
