Neural tube defects (NTD), resulting from a failure in the transformation of a flat neural plate into a closed neural tube, occur in approximately one in every thousand births. When the anterior neural tube fails to close, it results in a fatal birth defect called anencephaly in which the brain and skull fail to develop. Our long-term goal is to use zebrafish to define the genetic and cellular mechanisms that control closure of the anterior neural tube. We found that zebrafish embryos with reduced Nodal signaling have a phenotype analogous to anencephaly. The role of Nodal signaling is not within the neural tube itself, but within the head mesendoderm, a combined mesodermal and endodermal tissue that underlies the anterior neural tube. Rescue of head mesendoderm in Nodal signaling mutants effectively corrects their NTD. Head mesendoderm/mesoderm has a conserved role in anterior neurulation in vertebrates, but this role is poorly understood. This proposal will test the hypothesis that hea mesendoderm in zebrafish is required during late blastula to early gastrulation stages to initiate organization of neural tube precursors into a polarized neuroepithelium. Our objectives are to: (1) identify the sequential biochemical changes that establish adherens junctions, tight junctions, and asymmetric protein localization in the developing neuroepithelium, (2) define which of these biochemical changes depend upon head mesendoderm, (3) map when and where during development mesendoderm functions to promote anterior neurulation, and (4) test candidate proteins for essential roles in mediating mesendoderm function. These experiments will identify new roles for head mesendoderm in the development of the neural tube. Further, as the processes that drive neurulation are largely conserved between species, this research will increase our understanding of normal development and give us insight into potential causes of anencephaly in humans. Importantly, the hypothesis-driven experiments in this proposal are designed to be carried out by undergraduate students. They rely on well established techniques that have been mastered many undergraduate students in my laboratory. Further, the experiments are divided into specific sections that each rely on one molecular technique. This will enable students to take a project from beginning to publication within the time frame of their undergraduate studies. It is expected that this project will give undergraduate students valuable experience with the field of developmental genetics that will provide the basis for their future careers and studies while making important contributions to the science in my laboratory and to the understanding of the mechanisms underlying neurulation.

Public Health Relevance

Failures in neural tube closure are some of the most common birth defects in humans, but the causes are not well understood. We will use the genetic and embryological techniques available in zebrafish to uncover new mechanisms required for neural tube closure. As the cellular mechanisms that drive formation of the neural tube are largely conserved among vertebrate species, this work will provide insights into new ways to diagnose and treat neural tube defects in humans.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
1R15HD068176-01A1
Application #
8263926
Study Section
Special Emphasis Panel (ZRG1-CB-Z (90))
Program Officer
Henken, Deborah B
Project Start
2012-05-01
Project End
2015-04-30
Budget Start
2012-05-01
Budget End
2015-04-30
Support Year
1
Fiscal Year
2012
Total Cost
$456,000
Indirect Cost
$156,000
Name
University of Minnesota Duluth
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
071508873
City
Duluth
State
MN
Country
United States
Zip Code
55812