Zfp423 marks a pathway in control of neural precursor proliferation and renewal

WA Alcaraz, E Raponi, BA Hamilton
University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0644, United States of America

nur12 mutant mice have congenital defects of the CNS midline, including a striking agenesis of the cerebellar vermis that is reminiscent of certain human malformations. We identified a nonsense mutation of the transcription factor Zfp423 in nur12 by positional cloning. Zfp423 is an important cofactor for both BMP-activated SMADs and EBF transcription factors, which promote cell cycle exit and differentiation of neural precursor cells. Loss of Zfp423 results in reduced proliferation and abnormal differentiation of precursors in both cerebellar germinal zones. We interpret this as a disruption of the balance between self renewal and maturation of neural precursors, leading to nearly complete loss of the cerebellar vermis in nur12 animals. Surprisingly, cerebellar hemispheres are strongly affected in some strain backgrounds, leading to nearly complete loss of the cerebellum. In order to better understand the molecular mechanisms behind this striking range of brain malformations, we have begun genome-wide linkage mapping for potential major effect loci in two different strain pair crosses. Preliminary data from one cross identifies a single major peak (LOD = 5.7). None of the annotated genes under this peak are known components of either the BMP/Smad or EBF signaling pathways. Further analysis should extend our understanding of midline and lateral signaling during brain development.