This application describes an interdisciplinary approach involving basic and clinical scientists employing new and innovative informatic, genetic and developmental strategies to identify the underlying pathogenesis and causative genes for Dandy-Walker malformation, the most common structural malformation of the cerebellum. Dandy-Walker malformation is common, affecting 1/3000 live births and causes significant motor and intellectual delay and yet is poorly understood. Our group has identified the only 2 characterized loci for this clinically and genetically heterogeneous birth defect. Our analysis of mouse models has lead us to the hypothesis that disruption of mesenchymal signaling to the developing cerebellum is critical to the developmental pathogenesis of this birth defect. The recognition that the meninges is a critical regulator of CNS development is a recent paradigm shift in the field of neurodevelopment and the basic biology and molecular pathways of these interactions is not known. Further, it has become apparent that disrupted meningeal signaling underlies not only the significant clinical phenotypes of posterior fossa disorders such as Dandy-Walker, but has broad implications for the pathogenesis of large group of neurodevelopmental disorders that also involve meningeal signaling including ACC and others. The experiments outlined in this proposal are designed to identify pathways and mechanisms for posterior fossa mesenchymal regulation of cerebellar development, using Foxc1, the most recently identified Dandy-Walker gene, as an entry point.
Aims 1 -3 use novel in vitro and in vivo assays including explant culture, electroporation, RNAi and BAC transgenesis together with extensive informatic analyses to identify and validate the signaling pathways from the posterior fossa to the adjacent developing cerebellum which modulate Dandy-Walker related phenotypes in mouse models.
In Aim 4 we will then sequence the best Dandy-Walker candidates from the first 3 Aims, in a cohort of human Dandy-Walker patients to identify new disease-causative genes. Together these synergistic mouse and human experiments will define new biology regarding mesenchymal control of neural development and identify new DWM genes, which will immediately improve diagnosis for affected families and will be essential for future prognostic studies.

Public Health Relevance

This application develops and implements innovative interdisciplinary approaches to identify and characterize the developmental and genetic disruptions that cause Dandy-Walker malformation spectrum birth defects. Dandy-Walker malformation spectrum birth defects are structural birth defects of the developing cerebellum of the brain. They are common, affecting approximately 1/3000 live births and cause intellectual and motor delays and hydrocephalus. Through gene discovery, we aim to develop badly needed effective diagnostic and prognostic tools for affected families.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS080390-03
Application #
8667344
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Riddle, Robert D
Project Start
2012-09-15
Project End
2017-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
3
Fiscal Year
2014
Total Cost
$438,021
Indirect Cost
$212,237
Name
Seattle Children's Hospital
Department
Type
DUNS #
048682157
City
Seattle
State
WA
Country
United States
Zip Code
98105
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Millen, Kathleen J; Steshina, Ekaterina Y; Iskusnykh, Igor Y et al. (2014) Transformation of the cerebellum into more ventral brainstem fates causes cerebellar agenesis in the absence of Ptf1a function. Proc Natl Acad Sci U S A 111:E1777-86
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