Understanding the mechanism by which neural precursors make the switch between proliferation and cell cycle exit is the key to understanding human cerebellar malformations. This proposal will make use a of mouse model that resembles Dandy-Walker malformations. Mice homozygous for the nur12 mutation, which has been mapped to a zinc finger transcription factor Zfp423, have agenesis of the cerebellar vermis with varying degrees of hemisphere hypoplasia. Similar to Dandy-Walker malformation these mice also have reduced choroid plexus, anterior rotation of the cerebellum, enlargement of the fourth ventricle, and hydrocephaly. Preliminary data shows that the reduction in size of the cerebellum is due to reduced proliferation of precursor cells within the cerebellum. The three specific aims will (1) determine if reduced proliferation is due to reduction in the rate of proliferation or reduced probability of cell-cycle re-entry by consecutive labeling of different thymidine analogs and proliferation markers, and (2) determine genetic interactions that affect the degree of hemisphere hypoplasia in nur12 homozygotes by modifier mapping and RNA profiling.

Public Health Relevance

This proposal will identify mechanisms relevant to Dandy-Walker Malformation, a severe defect found in 1/25,000 - 1/30,000 births. Preliminary data suggests the mechanisms acting here regulate the switch between continued division of precursor cells and differentiation into mature cells, an important process in development, in which errors can lead to malformations or cancers.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31NS061513-02
Application #
7630449
Study Section
Special Emphasis Panel (ZRG1-F03A-M (20))
Program Officer
Owens, David F
Project Start
2008-07-01
Project End
2009-10-31
Budget Start
2009-07-01
Budget End
2009-10-31
Support Year
2
Fiscal Year
2009
Total Cost
$12,736
Indirect Cost
Name
University of California San Diego
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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