TFAP2 paralogs regulate midfacial development in part through a conserved ALX genetic pathway.

Area of Science:

• Developmental biology
• Genetics
• Molecular biology

Background:

• Cranial neural crest development relies on gene regulatory networks (GRNs).
• Understanding midfacial GRN activation and connections is limited.
• Facial shape variation arises from fine-tuning GRN components.

Approach:

• Investigated the role of Transcription factor AP2 (TFAP2) in murine neural crest development.
• Utilized bulk and single-cell RNA-sequencing (RNA-seq) and ChIP-sequencing (ChIP-seq).
• Examined TFAP2 and ALX gene interactions in mouse and zebrafish models.

Key Points:

• Concerted inactivation of Tfap2a and Tfap2b in mice caused midfacial clefts and skeletal defects.
• Loss of TFAP2 dysregulated midfacial GRN components essential for fusion, patterning, and differentiation.
• TFAP2 directly and positively regulates ALX gene expression, crucial for midface development.
• This regulatory axis is conserved across vertebrates, as shown in zebrafish.

Conclusions:

• TFAP2 plays a critical role in vertebrate midfacial development.
• TFAP2 regulates midfacial development partly through controlling ALX transcription factor gene expression.
• This study elucidates a key regulatory mechanism in craniofacial development.