Retinoic Acid Informs the Positional Identity of Frontonasal Neural Crest Cells Through Alx Family of Transcription Factors
Source: PubMed Central Open Access, NCBI / U.S. National Library of Medicine
ABSTRACT Cranial neural crest cells (CNCCs) give rise to the majority of the skeletal elements of the face. The precise morphogenesis of the face relies on highly coordinated actions of CNCCs, requiring each CNCC to obtain correct positional identity. As a diffusive signaling molecule, retinoic acid (RA) is known to regulate the positional identities along the anterior–posterior axis of the developing hindbrain by activating the Hox family of transcription factors. However, whether RA also has a direct role in regulating the positional identities of Hox‐negative CNCCs, which give rise to the skeletal framework of the face, was unclear. In this study, we show that RA acts as a local environmental cue that patterns the Hox‐negative CNCCs by activating the Alx family of transcription factors. We observed midfacial dysplasia and midline facial clefting in chick embryos after blocking RA signaling with an inverse pan‐RAR agonist. Gene expression analysis revealed that this morphological defect is associated with the transformation of frontonasal neural crest identity toward a first pharyngeal arch (PA1)‐like identity, a patterning defect that was also observed inandcompound mutant mouse embryos. We further showed that bothandare regulated by RA through cell‐autonomous RA receptor (RAR) signaling. Mechanistically, RA signaling regulatesthrough an evolutionarily conserved distal enhancer located upstream ofwithin the intronic region of the gene, whereas the RA‐responsiveness ofis co
Abstract
ABSTRACT Cranial neural crest cells (CNCCs) give rise to the majority of the skeletal elements of the face. The precise morphogenesis of the face relies on highly coordinated actions of CNCCs, requiring each CNCC to obtain correct positional identity. As a diffusive signaling molecule, retinoic acid (RA) is known to regulate the positional identities along the anterior–posterior axis of the developing hindbrain by activating the Hox family of transcription factors. However, whether RA also has a direct role in regulating the positional identities of Hox‐negative CNCCs, which give rise to the skeletal framework of the face, was unclear. In this study, we show that RA acts as a local environmental cue that patterns the Hox‐negative CNCCs by activating the Alx family of transcription factors. We observed midfacial dysplasia and midline facial clefting in chick embryos after blocking RA signaling with an inverse pan‐RAR agonist. Gene expression analysis revealed that this morphological defect is associated with the transformation of frontonasal neural crest identity toward a first pharyngeal arch (PA1)‐like identity, a patterning defect that was also observed inandcompound mutant mouse embryos. We further showed that bothandare regulated by RA through cell‐autonomous RA receptor (RAR) signaling. Mechanistically, RA signaling regulatesthrough an evolutionarily conserved distal enhancer located upstream ofwithin the intronic region of the gene, whereas the RA‐responsiveness ofis conferred by its promoter. These findings establish a mechanistic linkage between RA signaling and Alx genes and provide novel insights into the craniofacial defects associated with disrupted RA signaling. Retinoic acid (RA) regulates the positional identity of cranial neural crest cells (CNCCs) through the transcription factorsand. Upon receiving RA from the local environment, liganded RAR/RXR heterodimers activate the expression ofand, which promote the frontonasal identity of CNCCs and inhibit the first pharyngeal arch identity of CNCCs. graphical