reproduced verbatim): The goals of this proposal are to understand how posterior regions of the nervous system (hindbrain and spinal cord) are initially determined in vertebrates, using the zebrafish as a paradigm. The zebrafish is a wonderful model, allowing analysis of the early, crucial stages of nervous system development, by both embryological and genetic analysis. Integral to this study is a set of genes that we isolated by subtractive cloning, and that is expressed exclusively in the posterior of the embryo during gastrulation, when neural patterning has begun but before neural differentiation has occurred. Some of the genes isolated contain DNA binding motifs, while some are novel, suggesting that we have enriched for regulatory genes. This application has three parts. First, using these genes as markers, the tissues responsible for posterior neural induction will be determined, using explant assays that were developed for zebrafish in my laboratory. Second, the factors required for induction of posterior neural tissue will be analyzed using zebrafish mutants and dominant negative proteins. Third, the function of a subset of genes isolated by subtraction will be addressed. Genes will be placed on the zebrafish genetic map to determine whether they correspond to known mutations. Gain of function assays will ask how the novel nlz gene modulated posterior neural patterning. This application will define the cell interactions and genes required for normal hindbrain and spinal cord development. Normal brain development and health require integration of all parts of the nervous system, suggesting that deficits in the posterior nervous system may contribute to or exacerbate malfunction of other brain regions. The genes to be studied here may also help define the genetic basis of neural tube birth defects.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH059942-02
Application #
6392501
Study Section
Special Emphasis Panel (ZRG1-MDCN-6 (02))
Project Start
2000-05-15
Project End
2005-04-30
Budget Start
2001-05-01
Budget End
2002-04-30
Support Year
2
Fiscal Year
2001
Total Cost
$271,250
Indirect Cost
Name
Whitehead Institute for Biomedical Research
Department
Type
DUNS #
076580745
City
Cambridge
State
MA
Country
United States
Zip Code
02142
Lowery, Laura Anne; Sive, Hazel (2009) Totally tubular: the mystery behind function and origin of the brain ventricular system. Bioessays 31:446-58
Lowery, Laura Anne; De Rienzo, Gianluca; Gutzman, Jennifer H et al. (2009) Characterization and classification of zebrafish brain morphology mutants. Anat Rec (Hoboken) 292:94-106
Wardle, Fiona C; Odom, Duncan T; Bell, George W et al. (2006) Zebrafish promoter microarrays identify actively transcribed embryonic genes. Genome Biol 7:R71
Sagerstrom, Charles G; Gammill, Laura S; Veale, Robin et al. (2005) Specification of the enveloping layer and lack of autoneuralization in zebrafish embryonic explants. Dev Dyn 232:85-97
Lowery, Laura Anne; Sive, Hazel (2005) Initial formation of zebrafish brain ventricles occurs independently of circulation and requires the nagie oko and snakehead/atp1a1a.1 gene products. Development 132:2057-67
Wiellette, Elizabeth; Grinblat, Yevgenya; Austen, Matthias et al. (2004) Combined haploid and insertional mutation screen in the zebrafish. Genesis 40:231-40
Hoyle, Jacqueline; Tang, Yixin P; Wiellette, Elizabeth L et al. (2004) nlz gene family is required for hindbrain patterning in the zebrafish. Dev Dyn 229:835-46
Wiellette, Elizabeth L; Sive, Hazel (2004) Early requirement for fgf8 function during hindbrain pattern formation in zebrafish. Dev Dyn 229:393-9
Lowery, Laura Anne; Sive, Hazel (2004) Strategies of vertebrate neurulation and a re-evaluation of teleost neural tube formation. Mech Dev 121:1189-97
Tropepe, V; Sive, H L (2003) Can zebrafish be used as a model to study the neurodevelopmental causes of autism? Genes Brain Behav 2:268-81

Showing the most recent 10 out of 11 publications