Zfp423 controls proliferation and differentiation of neural precursors in cerebellar vermis formation

Abstract

Malformations affecting the cerebellar vermis are only poorly understood at the genetic level. Dandy-Walker malformations (DWM) are characterized by dilation of the fourth ventricle, anterior rotation of the cerebellum, vermis hypoplasia or agenesis, and hydrocephalus, and they may occur together with other abnormalities (1). Recent work identified a subset of DWM patients carrying interstitial deletions on chromosome 3, most of which were hemizygous for both ZIC1 and ZIC4 (2), transcription factors that promote proliferation of cerebellar granule cell precursors. Mice heterozygous for both Zic1 and Zic4 reproduce several DWM phenotypes, but show more modest effects on other characteristic features (2). Identifying genes with related phenotypes should help to clarify the developmental mechanisms behind such malformations.The nur12 mouse was identified as having an ataxic gait and cerebellar hypoplasia, including agenesis of the vermis, in a large chemical mutagenesis screen (3). Here, we use positional cloning and noncomplementation with a gene trap allele to identify the Ebf-and SMAD-interacting 30 zinc-finger protein, Zfp423 (also known as ROAZ or OAZ) as the gene mutated in nur12 mice. Tsai and Reed (4, 5) first described ROAZ in rat olfactory tissue as an Ebf1 (previously OLF-1, or O/E-1)-interacting protein identified in a yeast two-hybrid assay. Based on the overlapping temporal sequence of Zfp423 and Ebf1 expression in olfactory precursors, they proposed that their interaction maintains olfactory precursors in an immature state, whereas release of Ebf to form homodimers promotes terminal differentiation. Subsequent genetic manipulations indicated that Ebf family members promote neuronal differentiation coupled to cell cycle exit and migration out of germinal zones (6-10). Our results show that Zfp423 is required for proliferation and differentiation by precursor cells in the developing brain. We propose that by forming mutually exclusive complexes with other transcription factors, Zfp423 sharpens the response of precursor cells to external differentiation signals. The phenotypic similarities between nur12 mutant cerebellum and DWM may shed further light on a group of human disorders for which few genetic clues have been found. Results Ataxia and Brain Malformations in nur12Mice. Homozygous nur12 mice have ataxia and tremor [see supporting information (SI) Movie 1] and have a malformation of the cerebellum that is more severe at the vermis than the hemispheres (Fig. 1A) and a pronounced anterior rotation of the cerebellum within the posterior fossa (Fig. 1B). These features are characteristic of certain human hindbrain malformations, including DWM and cerebellar vermis hypoplasia (CVH), but are not common among ataxic mouse mutations. Among intercross progeny, the nur12 cerebellum can range from complete loss of vermis with somewhat smaller hemispheres to almost complete loss of the cerebellum. Within

Voltage-Gated Na+Channel β1 Subunit-Mediated Neurite Outgrowth Requires Fyn Kinase and Contributes to Postnatal CNS DevelopmentIn Vivo

“…5A). The outer proliferating zone (PZ) of the EGL contained the majority of BrdU-positive cells, consistent with BrdU incorporation into DNA of proliferating CGN precursors recently in S-phase (Alcaraz et al, 2006). The thickness of the PZ, defined by the lateral extent of the BrdU-positive cell nuclei, was unchanged between Scn1b wild-type and null mice (Fig.…”

Cyclin D1 and CDK4 Activity Contribute to the Undifferentiated Phenotype in Neuroblastoma

“…Zfp423 is a newly identified transcription factor controlling proliferation and differentiation of neural precursors in cerebellar vermis formation. MYT1 is a transcription factor that has a role in the regeneration of oligodendrocyte lineage cells in response to demyelination (35,36).…”

Multiple developmental programs are altered by loss ofZic1andZic4to cause Dandy-Walker malformation cerebellar pathogenesis

“…-/-mutants, we observed abnormal positioning of the preculminate fissure, resulting in reduction of the anterobasal domain in mutant cerebella. The relationship between cerebellar growth and foliation is complex as the two processes occur during roughly the same developmental period and are often both affected in cerebellar mutants (Alcaraz et al, 2006;Cheng et al, 2010;Corrales et al, 2006;Lewis et al, 2004;Satokata et al, 2000;Sillitoe and Joyner, 2007). Furthermore, analysis of conditional mutants in the Shh pathway has shown that reduction of Shh signaling produces a range of foliation phenotypes in addition to size deficits (Corrales et al, 2006).…”