Developmental defects of the cerebellum in humans have received less attention than other brain malformations such as neural tube defects and cortical malformations. Yet, cerebellar malformations are common, affecting approximately 1/5000 births. Dandy-Walker Malformation (DWM) and cerebellar vermis hypoplasia (CVH- also known as Dandy-Walker Variant) are the most frequent cerebellar malformations, and affected individuals often have motor deficits, mental retardation, and some have hydrocephalus. Although the specific causes of these clinically important birth defects remain largely undefined, there is evidence for considerable genetic heterogeneity and complex inheritance. Based on physical mapping of chromosomal abnormalities in patients, we have identified 3 loci harboring human cerebellar malformation genes: on chromosomes 3q24, 6p25 and 7q36. This proposal describes a series of experiments aimed at understanding the developmental mechanisms leading to the structural cerebellar and posterior fossa abnormities associated with these loci through the study of several mouse models. We have previously demonstrated that heterozygous co-deletion of the closely linked ZIC1/4 genes on chromosome 3q24 causes DWM.
Aim 1 of this proposal describes a series of genetic experiments in mice to assess the developmental pathways regulated by these Zic genes and a set of in vitro analyses to determine the physical nature of Zic1and Zic4 protein interactions underlying the observed genetic interaction. The experiments in Aim 2 are designed to define the basis of 6p25 DWM, through phenotypic characterization of both null and conditional mouse mutants of a candidate gene influencing both posterior fossa mesenchymal and cerebellar development. Further, genetic interactions between the 3q24 and 6p25 loci will be assessed. Finally, Aim 3 describes a series of transgenic experiments to determine the gene(s) and underlying developmental disruption causing severe CVH in a patient with a small genomic duplication of 7q36. Since similar mechanisms underlie both mouse and human CNS development, analysis of these mice will to determine the underlying molecular and developmental causes of human cerebellar malformations. This information is critical to the identification of additional malformation loci.
Sajan, Samin A; Fernandez, Liliana; Nieh, Sahar Esmaeeli et al. (2013) Both rare and de novo copy number variants are prevalent in agenesis of the corpus callosum but not in cerebellar hypoplasia or polymicrogyria. PLoS Genet 9:e1003823 |
Aldinger, Kimberly A; Elsen, Gina E; Prince, Victoria E et al. (2009) Model organisms inform the search for the genes and developmental pathology underlying malformations of the human hindbrain. Semin Pediatr Neurol 16:155-63 |
Barkovich, A James; Millen, Kathleen J; Dobyns, William B (2009) A developmental and genetic classification for midbrain-hindbrain malformations. Brain 132:3199-230 |