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.
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.
|Lin, Charles Y; Erkek, Serap; Tong, Yiai et al. (2016) Active medulloblastoma enhancers reveal subgroup-specific cellular origins. Nature 530:57-62|
|Tully, Hannah M; Ishak, Gisele E; Rue, Tessa C et al. (2016) Two Hundred Thirty-Six Children With Developmental Hydrocephalus: Causes and Clinical Consequences. J Child Neurol 31:309-20|
|Di Donato, Nataliya; Jean, Ying Y; Maga, A Murat et al. (2016) Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly with a Rare Lissencephaly Variant. Am J Hum Genet 99:1117-1129|
|Leto, Ketty; Arancillo, Marife; Becker, Esther B E et al. (2016) Consensus Paper: Cerebellar Development. Cerebellum 15:789-828|
|Haldipur, Parthiv; Gillies, Gwendolyn S; Janson, Olivia K et al. (2014) Foxc1 dependent mesenchymal signalling drives embryonic cerebellar growth. Elife 3:|
|French, Curtis R; Seshadri, Sudha; Destefano, Anita L et al. (2014) Mutation of FOXC1 and PITX2 induces cerebral small-vessel disease. J Clin Invest 124:4877-81|
|Chervenak, Andrew P; Bank, Lisa M; Thomsen, Nicole et al. (2014) The role of Zic genes in inner ear development in the mouse: Exploring mutant mouse phenotypes. Dev Dyn 243:1487-98|
|Doherty, Dan; Millen, Kathleen J; Barkovich, A James (2013) Midbrain and hindbrain malformations: advances in clinical diagnosis, imaging, and genetics. Lancet Neurol 12:381-93|
|Nieman, Brian J; Blank, Marissa C; Roman, Brian B et al. (2012) If the skull fits: magnetic resonance imaging and microcomputed tomography for combined analysis of brain and skull phenotypes in the mouse. Physiol Genomics 44:992-1002|