The University of Chicago Research Funding

• Principal Investigator: Kathleen Millen, PhD, Associate Professor, Department of Human Genetics; Committee on Genetics; Developmental Biology; Committee on Neurobiology; Cancer Center
• Start Date: September 15, 2009
• Total Award Amount: $402,605

Public Health Relevance

This proposal is focused on defining the etiology of human cerebellar malformations - common birth defects of the brain affecting 1/5000 births, associated with mental retardation and motor deficits. Inadequate knowledge regarding these malformations often results in mistaken diagnosis and inaccurate counseling regarding prognosis, management and the genetic recurrence risks. An improved understanding of the developmental and genetic causes will provide valuable diagnostic and prognostic information that will greatly influence treatment and genetic counseling.

Project Description

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) is the most frequent cerebellar malformation. Affected individuals often have motor deficits, mental retardation, autism and some have hydrocephalus. Although the specific causes of this clinically important birth defect 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 2 loci harboring human DWM on chromosomes 3q24 and 6p25.

This proposal describes a series of experiments aimed at understanding the developmental mechanisms leading to DWM pathology 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 Zic1/4 mutant mice to assess the developmental pathways regulated by these Zic genes. 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. 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 DWM. This information is critical to the identification of additional human DWM loci.

This award is funded under the American Recovery and Reinvestment Act of 2009, NIH Award number: 2R01NS050386-05A2