Holoprosencephaly (HPE) is the most common embryologic malformation of the forebrain in humans caused by incomplete cleavage of the prosencephalon. This malformation which affects the development of the prechordal plate and anterior neuroectoderm includes various degrees of midline fusion and cyclopia affecting the forebrain and face. Various genetic factors and environmental agents contribute to the etiology of HPE. In humans, mutations in the SIX3 gene encoding a homeodomain transcription factor have been associated with HPE. The genetic and cellular mechanisms of SIX3-promoted HPE are poorly understood. It remains unclear whether mutant SIX3 proteins have hypomorphic, antimorphic, or neomorphic activity. SIX3 mutations cause HPE in a dominant manner but with variable penetrance and expressivity, a finding that suggests that S/X3 interacts with other genetic loci. Functional inactivation of Six3 in mice has shown that repression of Wnt signaling in the anterior neuroectoderm is essential for vertebrate forebrain development; however, S/x3-heterozygous mice did not exhibit any obvious morphologic alteration. In this application, we propose to employ a combination of genetic, embryologic, and molecular methods to reproduce and characterize the HPE/cyclopia phenotype in mouse and zebrafish.
Aim 1 entails in vivo and in vitro molecular and transcriptional characterization of the generated HPE Six3 mutant proteins.
Aim 2 will generate zebrafish and mouse models of Six3-mediated HPE. We will use these models to identify tissues and genetic pathways affected by mutant Six3.
Aim 3 focuses on the identification of genes that cooperate with mutated Six3 in promoting HPE. These proposed studies will advance our understanding of the signaling pathways affected by HPE-Six3 mutations and, ultimately, will provide additional information to be used with the genetic counseling of human carriers of HPE-SIX3 mutations and decrease the frequency of these birth defects. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS052386-02
Application #
7204140
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Gwinn, Katrina
Project Start
2006-04-01
Project End
2010-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
2
Fiscal Year
2007
Total Cost
$349,339
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
Carlin, Dan; Sepich, Diane; Grover, Vandana K et al. (2012) Six3 cooperates with Hedgehog signaling to specify ventral telencephalon by promoting early expression of Foxg1a and repressing Wnt signaling. Development 139:2614-24
Geng, Xin; Oliver, Guillermo (2009) Pathogenesis of holoprosencephaly. J Clin Invest 119:1403-13
Geng, Xin; Speirs, Christina; Lagutin, Oleg et al. (2008) Haploinsufficiency of Six3 fails to activate Sonic hedgehog expression in the ventral forebrain and causes holoprosencephaly. Dev Cell 15:236-47
Jeong, Yongsu; Leskow, Federico Coluccio; El-Jaick, Kenia et al. (2008) Regulation of a remote Shh forebrain enhancer by the Six3 homeoprotein. Nat Genet 40:1348-53
Inbal, Adi; Kim, Seok-Hyung; Shin, Jimann et al. (2007) Six3 represses nodal activity to establish early brain asymmetry in zebrafish. Neuron 55:407-15
Geng, Xin; Lavado, Alfonso; Lagutin, Oleg V et al. (2007) Expression of Six3 Opposite Strand (Six3OS) during mouse embryonic development. Gene Expr Patterns 7:252-7