DESCRIPTION (provided by applicant): The OEIS complex is an association of malformations in human fetuses and babies primarily affecting the bladder, distal digestive tract, and vertebral skeleton. It and a broader spectrum of malformations called the 'lower mesodermal defects sequence," comprise a relatively common sporadic cause of stillbirth, perinatal lethality, and surgically-correctable birth defects. Very little is currently understood about the genetic or developmental etiology of this collection of malformations. This application will use a targeted mutation in the cytoplasmic signaling modulator Dact1 as an animal model for OEIS and related malformations. Dact1 mutant animals die shortly before or after birth from combined defects in the infraumbilical abdominal wall, the distal urogenital system, the anus, and the caudal vertebral column. Dact1 is expressed at early embryonic stages in mesodermal tissues. I hypothesize that the Dact1 protein functions downstream of both WntSa and WntSa intercellular signaling to influence mesoderm development, and that this secondarily affects the endoderm necessary for formation of the bladder, genitalia, and anus. This hypothesis provides a single hit genetic model for OEIS and the lower mesodermal defects sequence. We will test this hypothesis by making use of constitutive and mesoderm-specific Dact1 mutant mouse lines created in my laboratory, in combination with other mouse lines that alter and monitor Wnt signaling. The specific aims are: (1) To determine the role of Dact1 in Wnt5a-dependent signaling and mesoderm proliferation, migration and survival, (2) To determine the role of Dact1 in WntSa-dependent signaling and mesoderm differentiation, and (3) To use Dact1 mutants as a model for defects in mesodermal plus hindgut derivatives. The research design draws on the tremendous genetic, molecular, and embryonic experimental resources available in the laboratory mouse. It will probe contributions of the Dact1 gene to mesoderm and endoderm development, the signaling pathways involved, and how disruptions in Dact1 function lead to complex caudal malformations in neonates. This research is important to public health because it creates, establishes, and uses a new animal model to investigate the origins of a series of complex birth defects in humans. Our studies of the Dact1 mouse will help uncover the genetic, molecular, and cellular basis for birth defects that contribute significantly to still-births, infant deaths, and neonatal surgeries in the United States.