アルクス1転写因子は、眼筋形成を規定するために初期頭蓋中胚葉で作用する

Loss of ALX1 gene function causes severe facial clefting and extreme microphthalmia. Previous studies suggest that ALX1 protein function is crucial for patterning the cranial neural crest cell (CNCC)-derived frontonasal mesenchyme, but how ALX1 regulates eye development is not well understood. Here, we show that Alx1 is transiently expressed in the embryonic cranial mesoderm and that Alx1-/- mice exhibit agenesis of extraocular muscles (EOMs) without affecting other muscles. We show that cranial mesoderm-specific Alx1 inactivation resulted in complete EOM agenesis accompanied by failure of activation of the core myogenic regulatory network specifically in, and increased apoptosis of, the EOM progenitor cells. Analysis of mice with temporally induced Alx1 inactivation demonstrated that EOM myogenesis requires Alx1 function before, but not after, formation of the EOM primordium. These data identify ALX1 as a unique and specific upstream regulator of EOM myogenesis, and provide new insights into pathogenic mechanisms underlying ALX1-type frontonasal dysplasia, as well as molecular mechanisms controlling cell fate specification in the early cranial mesoderm.