Genetic Control of Neural Development and Disease
Development and disease in the cerebellum.
The cerebellum is both a significant locus of human disease and an unusually tractable brain structure for genetic analysis. Through positional cloning and gene trap studies in mice we have identified transcriptional regulators required for proliferation of cerebellar progenitors (Zfp423) and for differentiation of the cerebellar Purkinje cells (Rora). Nur12 affects the decision of neural progenitors in both the fourth ventricular zone and rhombic lip/external germinal layer to remain in the cell cycle. Loss of this transcription factor results in a vermis malformation reminiscent of human disorders. RORa is required for differentiation and maintenance of Purkinje neurons, output neurons derived from the ventricular zone. Developmental RNA profiling and chromatin immunoprecipitation experiments identify direct transcriptional targets of RORa that strongly overlap with genes affected by Spinocerebellar ataxia type 1 (SCA1), a polyglutamine repeat expansion disorder, prior to degeneration of the Purkinje cells.
Genetic suppression of mRNA processing defects by a nuclear export factor.
Genetic analysis of other neurological mutations has lead us to a novel mechanism of genetic suppression. Endogenous retroviruses are a frequent cause of spontaneous mutations in mice. Integrations into introns where, RNA processing signals in the provirus quantitatively interfere with the normal processing of the interrupted host gene, are particularly common. We have shown that a naturally-occuring amino acid substitution allele of the mRNA nuclear export factor Nxf1 alters the balance of alternative processing of several unrelated retrovirus mutations. Population genetics indicates that Nxf1 has recently been under strong directional selection in wild mice, plausibly in response to an infectious RNA virus. New data suggests that the human NXF1 locus has also undergone positive selection, for expression level, in the human lineage.
Sympathetic control of blood pressure.
Sympathetic tone at neuroeffector junctions is a key regulator of blood pressure. In a collaborative case/control study of candidate genes for genetic susceptibility to hypertension we find evidence for susceptibility conferred by a variant in one of the granins, regulators or catecholaminergic vesicle function. The risk allele confers transcriptional enhancer activity and is bound in cells by paired-like homeobox proteins.
Modifier genes and the plasticity of genetic networks in mice. Hamilton, B. A. and Yu B. Y. (2012) PLoS Genetics In press.
Modifier genes and non-genetic factors reshape anatomical deficits in Zfp423-deficient mice. Alcaraz, W. A., Chen, E., Valdes, P., Kim, E., Lo, Y. H., Vo, J., and Hamilton, B. A. (2011) Human Molecular Genetics 20, 3822-3830. (Cover article)
Modifier genes for mouse phosphatidylinositol transfer protein alpha (vibrator) that bypass juvenile lethality. Concepcion, D., Johannes, F., Lo, Y. H., Yao, J., Fong, J., and Hamilton, B. A. (2011) Genetics 187, 1185-1191.
Multipotent genetic suppression of retrotransposon-induced mutations by Nxf1 through fine-tuning of alternative splicing. Concepcion, D., Flores-García, L., and Hamilton, B. A. (2009) PLoS Genetics 5, e1000484.