The well-conserved canonical and non-canonical Wnt pathways are important for all aspects of mammalian development, including the development of the central nervous system. An outstanding question remains: how are the various Wnt pathways that regulate development integrated in vivo? Dvls are outstanding candidates to address this question, since these conserved proteins are required in all eukaryotes for both canonical and non-canonical Wnt pathways. We have uncovered partially unique but predominantly redundant functions among the three Dvl genes. Single mutants display some unique defects in social behavior and conotruncal heart development, while double Dvl mutants display severe neural tube defects (craniorachischisis) and severe cochlear defects. In further support of redundancy, Dvl1/2/3 triple mutants are unable to undergo gastrulation and do not form mesoderm. We plan to dissect the in vivo pathways that Dvls regulate normal development and are disrupted in the Dvl mutants to produce these phenotypes. We produced in vivo conditional alleles in mice for each of the Dvl genes as well as in vivo alleles that can distinguish either canonical Wnt of non-canonical Wnt/PCP pathway function. We used these alleles to provide definitive evidence that the craniorachischisis phenotype displayed by Dvl1;Dvl2 double mutants resulted from disruption of convergent extension movements via the Wnt/PCP pathway. We will use these tools to provide a comprehensive analysis of the role of the canonical Wnt and non-canonical Wnt/PCP pathways during neuronal development from the first development of neural folds during gastrulation and neurulation throughout neurogenesis and neuronal migration. Based on our published and preliminary data, we predict that Dvls and the pathways they regulate are critical at all stages of brain development. We will use the following specific aims: 1) Determine the role of canonical Wnt and non-canonical Wnt/PCP pathways during gastrulation in vivo; 2) Characterize the Dvl dependent pathways responsible for neural tube closure during neurulation; 3) Determine the role of Dvls and the canonical Wnt and non-canonical Wnt/PCP pathways during forebrain/midbrain-hindbrain development using double Dvl mutants; and 4) Determine the role of Dvls and the canonical Wnt and non-canonical Wnt/PCP pathways during forebrain/midbrain-hindbrain development using triple Dvl mutants.

Public Health Relevance

Understanding cellular mechanisms and pathways that mediate neuronal development by the Wnt pathways using Dvl mutant mice will likely provide important insights into human neural tube defects and the development of the central nervous system. The use of sophisticated mouse mutants that inactivate each of the Dvls or express conditional or mutant alleles that express fluorescently tagged proteins will allow for the detailed study of these mechanisms and pathways in ways that are impossible in the human.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
7R01NS073159-10
Application #
8739102
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Morris, Jill A
Project Start
2012-12-01
Project End
2015-07-31
Budget Start
2013-08-03
Budget End
2014-07-31
Support Year
10
Fiscal Year
2013
Total Cost
$365,235
Indirect Cost
$134,803
Name
Case Western Reserve University
Department
Genetics
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Ohata, Shinya; Nakatani, Jin; Herranz-PĂ©rez, Vicente et al. (2014) Loss of Dishevelleds disrupts planar polarity in ependymal motile cilia and results in hydrocephalus. Neuron 83:558-71
Toyo-oka, Kazuhito; Wachi, Tomoka; Hunt, Robert F et al. (2014) 14-3-3? and ? regulate neurogenesis and differentiation of neuronal progenitor cells in the developing brain. J Neurosci 34:12168-81
Wang, Jianbo; Sinha, Tanvi; Wynshaw-Boris, Anthony (2012) Wnt signaling in mammalian development: lessons from mouse genetics. Cold Spring Harb Perspect Biol 4: