The staggering functional and anatomical complexity of the vertebrate brain arises gradually during embryonic development from an initially uniform field of cells. We would like to understand the early steps of brain development, in particular, formation of asymmetry along the dorsal/ventral axis of the brain primordium. This study will address the roles of two related transcription factors, zic2 and zic5, during dorsal brain formation. Important functions for both genes have already been demonstrated in several vertebrates, but their mechanisms are not understood. In humans, mutations in zic2 and zic5 have been causally linked to two prevalent birth defects: exencephaly and holoprosencephaly. Expression of zic genes is restricted to the dorsal portion of the neural tube, and this restriction is critical for their correct function. In spite of their obvious importance, the molecular mechanisms of regulation and function of vertebrate zic genes are not well understood. We have obtained exciting preliminary evidence that zic2 and zic5 regulate transcription of wntl, a gene with essential functions during dorsal brain formation, and that Wnt signaling in turn regulates transcription of zics. These data have led us to propose that wht and zic genes are involved in a regulatory feedback loop. This novel hypothesis will help explain at least some of the defects observed in zic mutants, and will be tested in a different model system, the zebrafish. Zebrafish embryos are available during all stages of brain development, are easy to observe and manipulate, and have a short generation time. As a result, powerful genetic, genomic and embryological methods have been established for use in this model organism. Strong evolutionary conservation of the zic gene family ensures that this study will uncover shared molecular mechanisms that operate during brain formation in all vertebrates, including humans. Ultimately, this work will contribute to a better understanding of the mechanisms underlying birth defects that affect embryonic development of the vetebrate brain.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM076244-03
Application #
7341075
Study Section
Development - 1 Study Section (DEV)
Program Officer
Haynes, Susan R
Project Start
2006-02-01
Project End
2011-01-31
Budget Start
2008-02-01
Budget End
2009-01-31
Support Year
3
Fiscal Year
2008
Total Cost
$246,374
Indirect Cost
Name
University of Wisconsin Madison
Department
Zoology
Type
Schools of Arts and Sciences
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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Teslaa, Jessica J; Keller, Abigail N; Nyholm, Molly K et al. (2013) Zebrafish Zic2a and Zic2b regulate neural crest and craniofacial development. Dev Biol 380:73-86
Goswami, Srikanta; Tarapore, Rohinton S; Teslaa, Jessica J et al. (2010) MicroRNA-340-mediated degradation of microphthalmia-associated transcription factor mRNA is inhibited by the coding region determinant-binding protein. J Biol Chem 285:20532-40
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Walters, Kevin B; Dodd, M Ernest; Mathias, Jonathan R et al. (2009) Muscle degeneration and leukocyte infiltration caused by mutation of zebrafish Fad24. Dev Dyn 238:86-99
Noubissi, Felicite K; Goswami, Srikanta; Sanek, Nicholas A et al. (2009) Wnt signaling stimulates transcriptional outcome of the Hedgehog pathway by stabilizing GLI1 mRNA. Cancer Res 69:8572-8
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Nyholm, Molly K; Wu, Shan-Fu; Dorsky, Richard I et al. (2007) The zebrafish zic2a-zic5 gene pair acts downstream of canonical Wnt signaling to control cell proliferation in the developing tectum. Development 134:735-46