Genes

Nxf1 encodes a nuclear export factor. Quantitative regulation of gene expression is complex. Initiation, elongation, processing, nuclear export, translation, and turnover of mRNA are generally coupled, but allow several points of control. We discovered that a wild-derived variant of mouse Nxf1 acts as a genetic suppressor of mutations caused by integration of an endogenous retrovirus by increasing the amount and proportion of correctly processed mRNA from the mutated gene, at the expense of mutation-specific, abnormal RNAs (Floyd 2003, Concepcion 2009). This suggests that Nxf1 can influence processing choices for at least some pre-mRNAs, in addition to its better-known recruitment to export complexes after processing. Genome editing in mice showed that a single amino acid substitution in the TAP_C domain is sufficient for this effect (Concepcion 2015). We are working to understand how Nxf1 variants alters gene expression and potentially remodel its protein interaction network. This work is funded by a grant from the National Institute for General Medical Sciences (NIGMS).

​Zfp423 encodes a protein with 30 "zinc finger" domains. This protein interacts with both lineage and signal-dependent transcription factors to repress or activate target genes. Mice that lack Zfp423 have midline defects in brain development, similar in kind to several human disorders (Alcaraz, 2006). The brain abnormalities are most apparent in cerebellum. We showed that variation in the phenotype results from both modifier genes and non-genetic causes (Alcaraz, 2011). Consistent with the mouse phenotype, the human homolog ZNF423 is mutated in patients with Joubert Syndrome related disorders (Chaki, 2012). Patient mutation confer abnormal DNA damage response to transfected cells (Chaki, 2012). Zfp423 has many likely sites of action and is expressed in a dynamic pattern during development. One important site is cerebellar granule cell precursors, where Zfp423 is required for proliferative response to SHH through the primary cilium (Hong, 2016). We are using custom mice to determine which Zfp423 phenotypes are cell autonomous, to model pathogenicity of genetic variants identified in patients, and to test for epistatic interactions between Zfp423 and its transcriptional targets. This work is funded by the National Institute for Neurolgical Disorders and Stroke (NINDS).

Zfp804a encodes a single zinc finger. Genome-wide studies by others identified ZNF804A as one gene associated with human psychiatric illness. While predicted to be a transcription factor, little is known about its functional properties, interaction partners, or effects on brain development. We have created custom mouse strains to allow visualization and purification of native Zfp804a and to test its requirements for normal development and behavior. This project is funded by the National Institute for Mental Health (NIMH).

Nmf9 encodes a protein of uncertain function. Mice that lack this gene have defects in vestibular function, fear learning, and precision of circadian behaviors (Zhang 2015). The gene is unusually conserved. The core protein sequence, gove of take a domain, is identifiable in unicellular organisms that are sister groups to animals. Invertebrate species from every major phylum have a single copy except for tunicates, which have none. Jawed vertebrates have two paralogous copies, with the derived version having lost an RA domain that is constant among invertebrates. Mammals have only the derived, deleted copy. Mutations introduced by genome editing in mice, zebrafish, and fruit flies all produce defects in movement and balance, suggesting a level of functional conservation. However, while mice lacking Nmf9 have a comparatively mild phenotype, flies that lack the gene have severe defects and die as pupae or young adults.