Disruptions in the normal development of the cerebellum result in clinically significant malformations whose mechanistic bases are poorly understood. This proposal uses a combination of established and emerging genetic and genomic methods to dissect molecular mechanisms of cerebellar vermis malformation in a new mouse model resembling Dandy-Walker malformations. Homozygotes for the nur12 mutation show show nearly complete agenesis of the vermis and choroid plexus, cystic dilation of the fourth ventricle, and anterior malrotation of cerebellar structures within the posterior fossa. As preliminary data for defining molecular mechanisms relevant to features shared between this mutant and human patients, the applicant has identified a null mutation of a zinc finger transcription in nur12 mutants. The applicant has begun to identify developmental sequelae to this mutation, including profound effects on proliferation of neural progenitor cells. The three specific aims will (1) establish an allelic series at the locus and investigate sources of interindividual variation in the severity (hemispheric involvement) of null allele;(2) define cellular and developmental mechanisms of the nur12 malformation, including tests for the roles of BMP/SMAD and EBF signaling pathway, through a combination of in situ labeling, marker gene analyses and signaling response measurements in culture;and (3) identify molecular targets of ZFP423 activity in cerebellum development by transcriptional profiling at sequential stages of development and by identifying overlaps in promoter occupancy among ZFP423, BMP-activated SMADs and EBF factors using a highly parallel platform for genome-wide location analysis for transcription factor binding. Relevance: This proposal will identify mechanisms relevant to the Dandy-Walker malformation - a severe defect found in 1/25,000 -1/30,000 births. Preliminary results suggest that the mechanisms acting here affect the ability of precursor cells to continue dividing, which may have therapeutic application for both prenatally diagnosed malformations and pediatric brain cancers.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Riddle, Robert D
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Diego
Internal Medicine/Medicine
Schools of Medicine
La Jolla
United States
Zip Code
Hong, Chen-Jei; Hamilton, Bruce A (2016) Zfp423 Regulates Sonic Hedgehog Signaling via Primary Cilium Function. PLoS Genet 12:e1006357
Cho, Young-Wook; Hong, Chen-Jei; Hou, Aiju et al. (2013) Zfp423 binds autoregulatory sites in p19 cell culture model. PLoS One 8:e66514
Chaki, Moumita; Airik, Rannar; Ghosh, Amiya K et al. (2012) Exome capture reveals ZNF423 and CEP164 mutations, linking renal ciliopathies to DNA damage response signaling. Cell 150:533-48
Hamilton, Bruce A; Yu, Benjamin D (2012) Modifier genes and the plasticity of genetic networks in mice. PLoS Genet 8:e1002644
Alcaraz, Wendy A; Chen, Edward; Valdes, Phoebe et al. (2011) Modifier genes and non-genetic factors reshape anatomical deficits in Zfp423-deficient mice. Hum Mol Genet 20:3822-30