KCTD1/KCTD15 complexes repress AP-2α and AP-2β to regulate neural crest-dependent craniofacial morphogenesis and...

KCTD1 and KCTD15 form pentameric complexes that regulate neural crest cell (NCC) and keratinocyte functions, and dominant-negative mutations in their genes cause aplasia cutis congenita and craniofacial abnormalities. Although KCTD1/KCTD15 complexes have been proposed to modulate multiple developmental pathways in vitro, the key downstream mechanisms responsible for these phenotypes in vivo remain unclear. In this study, we investigated the function of KCTD1/KCTD15 complexes specifically in NCCs. Using conditional mouse models, cell lineage tracing, and genetic epistasis approaches, we show that KCTD1/KCTD15 complexes regulate NCC-dependent craniofacial development and midline scalp skin formation primarily by repressing the transcriptional activity of AP-2α and AP-2β. Loss of KCTD1/KCTD15 in NCCs resulted in aplasia cutis congenita, cranial suture abnormalities, nasal bone hypoplasia, incisor agenesis, eyelid defects, pigmentation abnormalities, and cleft palate. Genetic reduction of AP-2α and AP-2β dosage in NCCs lacking KCTD1/KCTD15 markedly rescued these defects, establishing derepressed AP-2 activity as the principal pathogenic mechanism. Conversely, NCC-specific loss of AP-2α/AP-2β produced partially overlapping craniofacial defects, demonstrating that craniofacial morphogenesis is highly sensitive to AP-2 dosage. These findings identify a KCTD1/KCTD15-AP-2 regulatory axis as a central mechanism controlling neural crest-derived craniofacial development and scalp skin formation and establish aplasia cutis congenita as a neurocristopathy arising from dysregulated AP-2 activity.