Abstract
Chicken Ovalbumin Upstream Promoter-Transcription Factor II (COUP-TFII) plays pivotal roles in cell growth, cell differentiation, and cell fate determination. Although genome-wide studies have identified COUP-TFII binding on gene sets mainly involved in neural crest cell (NCC) development and craniofacial morphogenesis, the direct functional connection between COUP-TFII and NCCs in vivo has not been well characterized. In this study, we show that COUP-TFII is expressed in the subpopulation of NCCs and its derivatives, and targeted ablation of COUP-TFII in mouse NCCs results in markedly shortened and bifurcated tympanic rings, which in turn disturb the caudal direction of external acoustic meatus invagination. However, formation of the manubrium of the malleus (MM) in Wnt1-Cre/+;COUP-TFIIflox/flox mice is not perturbed, suggesting that the rostral half of the tympanic ring is sufficient to support proper MM development. Interestingly, we found that loss of COUP-TFII up-regulates Sox9 in the tympanic ring primordium and affects the distribution of preosteoblasts before mesenchymal condensation. Together, our results demonstrate that COUP-TFII plays an essential role in regulating the patterning of the NCC-derived tympanic ring.
Highlights
Neural crest cells (NCCs) are a multipotent, migratory cell population that is unique to vertebrates and is generated transiently during embryonic development
To explore whether COUP-TFII plays a physiological role in regulating development of the NCC lineage, we examined the spatiotemporal expression of COUP-TFII
Given that Sox[9] is required for determining chondrogenic cell lineage and is sufficient for cartilage formation[8,14,39,40], we investigated whether malformations of the tympanic ring in Wnt1-Cre/+;COUP-TFIIflox/flox mutants result from inaccurate cell fate decision due to abnormal up-regulation of Sox[9]
Summary
Neural crest cells (NCCs) are a multipotent, migratory cell population that is unique to vertebrates and is generated transiently during embryonic development. Based on the expression profiles of Sox[9] and Runx[2] at the mesenchymal condensation stage, a binary molecular code is proposed to predict the identity of skeletal tissues[14]. Genome-wide epigenomic profiling of chromatin landscapes, gene expression, and cis-element sequence analysis of human embryonic stem cell-derived NCCs revealed that TFAP2A, COUP-TFI, and COUP-TFII simultaneously co-occupy human NCC enhancers and facilitate establishment of a transcriptionally active chromatin enhancer state. The functional annotation of TFAP2A and COUP-TFI/COUP-TFII co-bound regions uncovered a strong association with NC gene expression, cranial NCC-derived structures, and craniofacial anomalies, suggesting that COUP-TFII regulates NC development and craniofacial morphogenesis[28,29]. Loss of COUP-TFII up-regulates the expression of Sox[9] in the tympanic ring primordium before mesenchymal condensation and affects the distribution of preosteoblasts, uncovering an essential role of COUP-TFII in the patterning of tympanic ring development. Our study provides new insights into the role of COUP-TFII in NCC-derived intramembranous bone formation
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