"One third of all human congenital malformations affects craniofacial development and represents a serious concern for society. Within the developing primordia, unique spatio temporal patterns of gene expression correlate with cellular and tissue fates, id entities and behaviours and therefore, morphogenesis.The goal of this proposal is to finely dissect the genetic control of craniofacial development with particular focus on CNC (cranial neural crest cell) cell specification and craniofacial morphogenesis b y Hox homeodomain proteins and their cofactors Pbx1 and Pbx2, through the following specific aims:1) Genetically dissect the early roles of Pbx1 in craniofacial patterning and morphogenesis.To achieve this goal, I will generate knockout mice where Pbx1 is inactivated in a tissue-specific manner in neural crest and in discrete head structures, by utilizing the Pbx1 conditional knockout mouse recently generated in the Selleri laboratory and available Cre mice.2) Identify in vivo genetic interaction of Pbx1 wi th specific Hox genes known to pattern craniofacial structures, such as Hoxa2.In order to uncover possible synergistic interactions of Pbx1 and Hoxa2, responsible for BA2 craniofacial patterning, I will cross Pbx1 and Hoxa2 mutant mice. By doing so, I will attempt to genetically dissect Hox-dependent as well as independent Pbx1 functions that control the BA2 programs. The Hoxa2 mice are made available for these studies by Dr. Rijli (Strasbourg- France).3) Identify genetic interactions and/or overlapping fun ctions of Pbx1 with related family member Pbx2 in craniofacial development.In order to test the possible genetic interactions and overlapping functions between Pbx1 and Pbx2 in craniofacial development, I will analyze CNC derived craniofacial structures in Pbx1/Pbx2 double mutant mice."