Development of neural circuitry depends on the integration of signaling pathways to coordinate specification, proliferation and differentiation of cell types in the right number, in the right place, at the right time. Zinc finger protein 423 (Zfp423), a 30-zinc finger transcription factor, forms alternate complexes with components of several developmental signaling pathways, suggesting it as a point of signal integration during brain development. We previously showed that mice lacking Zfp423 have reduced proliferation of cerebellar precursor cells, resulting in complete loss of vermis and variable hypoplasia of cerebellar hemispheres. Here, we show that Zfp423(-/-) hemisphere malformations are shaped by both genetic and non-genetic factors, producing distinct phenotype distributions in different inbred genetic backgrounds. In genetic mapping studies, we identify four additive modifier loci (Amzn1-4) and seven synthetically interacting loci (Smzn1.1-3.1) that together explain approximately one-third of the phenotypic variance. Strain-specific sequence polymorphism and expression data provide a reduced list of functional variant candidate genes at each modifier locus. Environmental covariates add only modest explanatory power, suggesting an additional stochastic component. These results provide a comprehensive analysis of sources of phenotype variation in a model of hindbrain malformation.

Zfp423 encodes a transcriptional regulatory protein that interacts with canonical signaling and lineage pathways. Mutations in mouse Zfp423 or its human ortholog ZNF423 are associated with a range of developmental abnormalities reminiscent of ciliopathies, including cerebellar vermis hypoplasia and other midline brain defects. Null mice have reduced viability in most strain backgrounds. Here we show complete lethality on a C57BL/6J background, dominant rescue in backcrosses to any of 13 partner strains, with strain-dependent survival frequencies, and evidence for a BALB/c-derived survival modifier locus on chromosome 5. Survival data indicate both perinatal and postnatal periods of lethality. Anatomical data from a hypomorphic gene trap allele observed on both C57BL/6J and BALB/c congenic backgrounds shows an aggregate effect of background on sensitivity to Zfp423 loss rather than a binary effect on viability.

Zfp423 encodes a transcriptional regulatory protein that interacts with canonical signaling and lineage pathways. Mutations in mouse Zfp423 or its human ortholog ZNF423 are associated with a range of developmental abnormalities reminiscent of ciliopathies, including cerebellar vermis hypoplasia and other midline brain defects. Null mice have reduced viability in most strain backgrounds. Here we show complete lethality on a C57BL/6J background, dominant rescue in backcrosses to any of 13 partner strains, with strain-dependent survival frequencies, and evidence for a BALB/c-derived survival modifier locus on chromosome 5. Survival data indicate both perinatal and postnatal periods of lethality. Anatomical data from a hypomorphic gene trap allele observed on both C57BL/6J and BALB/c congenic backgrounds shows an aggregate effect of background on sensitivity to Zfp423 loss rather than a binary effect on viability.

Background Mutations in PSEN1, PSEN2, and APP can lead to Alzheimer’s disease (AD) with an early age at onset (AAO) and hallmark progressive cognitive decline. These mutations are highly penetrant. Although mutations in PSEN1 are more common and usually have an earlier AAO, certain mutations in PSEN1 cause a later AAO, similar to PSEN2 and APP mutations. We sought to determine whether common disease endotypes exist across these mutations with a relatively late AAO. Methods We generated hiPSC-derived neurons from patients harboring autosomal-dominant, familial Alzheimer’s disease (FAD) mutations in PSEN1, PSEN2, and APP with a documented age at onset (AAO) around 55 years: PSEN1A79V, PSEN2N141I, and APPV717I. We carried out RNA-seq and ATAC-seq to mechanistically characterize the gene expression and chromatin accessibility changes, respectively. Differential expression analysis, enrichment analysis, TF activity identification, and co-expression module detection were performed for RNA-seq. Differential peak analysis and annotation, TF motif footprinting and differential motif accessibility, and peak functional enrichment were performed for ATAC-seq. This approach allowed us to identify the correlation between gene expression and chromatin accessibility associated with key disease endotypes. Results Using a multiomics approach, we identify and characterize common endotypes in mutations across all three FAD genes: dedifferentiation of a mature neuron to a less differentiated quasi-neuron state, dysregulation of synaptic signaling, repression of mitochondrial function and metabolism, and inflammation. The integrativeanalysis allowed us to ascertain the master transcriptional regulators associated with these endotypes, including REST, ASCL1, and ZIC family members (activation), as well as NRF1 (repression). Conclusions Our findings characterize the common regulatory changes within endotypes across these FAD mutations. However, the severity of dysregulation often differs between PSEN1, PSEN2, and APP mutations both in magnitude and direction. The overarching common link between mutations in FAD genes is the reversion to a less-differentiated neuron state. The transcriptional regulatory mechanisms described within disease endotypes offer potential targets for therapeutic interventions.