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.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
Project #
Application #
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Javois, Lorette Claire
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Francisco
Schools of Medicine
San Francisco
United States
Zip Code
Okerlund, Nathan D; Stanley, Robert E; Cheyette, Benjamin N R (2016) The Planar Cell Polarity Transmembrane Protein Vangl2 Promotes Dendrite, Spine and Glutamatergic Synapse Formation in the Mammalian Forebrain. Mol Neuropsychiatry 2:107-14
Yang, Xiaoyong; Fisher, Daniel A; Cheyette, Benjamin Nr (2013) SEC14 and Spectrin Domains 1 (Sestd1), Dishevelled 2 (Dvl2) and Dapper Antagonist of Catenin-1 (Dact1) co-regulate the Wnt/Planar Cell Polarity (PCP) pathway during mammalian development. Commun Integr Biol 6:e26834
Yang, XiaoYong; Cheyette, Benjamin N R (2013) SEC14 and spectrin domains 1 (Sestd1) and Dapper antagonist of catenin 1 (Dact1) scaffold proteins cooperatively regulate the Van Gogh-like 2 (Vangl2) four-pass transmembrane protein and planar cell polarity (PCP) pathway during embryonic development in m J Biol Chem 288:20111-20
Kivimae, Saul; Yang, Xiao Yong; Cheyette, Benjamin N R (2011) All Dact (Dapper/Frodo) scaffold proteins dimerize and exhibit conserved interactions with Vangl, Dvl, and serine/threonine kinases. BMC Biochem 12:33
Kettunen, Paivi; Kivimae, Saul; Keshari, Pankaj et al. (2010) Dact1-3 mRNAs exhibit distinct expression domains during tooth development. Gene Expr Patterns 10:140-3
Louie, Sarah H; Yang, Xiao Yong; Conrad, William H et al. (2009) Modulation of the beta-catenin signaling pathway by the dishevelled-associated protein Hipk1. PLoS One 4:e4310
Suriben, Rowena; Kivimäe, Saul; Fisher, Daniel A C et al. (2009) Posterior malformations in Dact1 mutant mice arise through misregulated Vangl2 at the primitive streak. Nat Genet 41:977-85
Jiang, Xia; Tan, Jing; Li, Jingsong et al. (2008) DACT3 is an epigenetic regulator of Wnt/beta-catenin signaling in colorectal cancer and is a therapeutic target of histone modifications. Cancer Cell 13:529-41