PAX6
Paired box protein Pax-6 (Aniridia type II protein) (Oculorhombin) [AN2]
PublicationsПравить
TALE-homeodomain proteins function as components of heteromeric complexes that contain one member each of the PBC and MEIS/PREP subclasses. We recently showed that MEIS2 cooperates with the neurogenic transcription factor PAX6 in the control of adult subventricular zone (SVZ) neurogenesis in rodents. Expression of the PBC protein PBX1 in the SVZ has been reported, but its functional role(s) has not been investigated. Using a genetic loss-of-function mouse model, we now show that Pbx1 is an early regulator of SVZ neurogenesis. Targeted deletion of Pbx1 by retroviral transduction of Cre recombinase into Pbx2-deficient SVZ stem and progenitor cells carrying floxed alleles of Pbx1 significantly reduced the production of neurons and increased the generation of oligodendrocytes. Loss of Pbx1 expression in neuronally committed neuroblasts in the rostral migratory stream in a Pbx2 null background, by contrast, severely compromised cell survival. By chromatin immunoprecipitation from endogenous tissues or isolated cells, we further detected PBX1 binding to known regulatory regions of the neuron-specific genes Dcx and Th days or even weeks before the respective genes are expressed during the normal program of SVZ neurogenesis, suggesting that PBX1 might act as a priming factor to mark these genes for subsequent activation. Collectively, our results establish that PBX1 regulates adult neural cell fate determination in a manner beyond that of its heterodimerization partner MEIS2.
MeSH Terms
- Aging
- Animals
- Base Sequence
- Cell Differentiation
- Cell Lineage
- Cell Movement
- Cell Survival
- Cells, Cultured
- Enhancer Elements, Genetic
- Gene Deletion
- Gene Expression Regulation, Developmental
- Gene Targeting
- Homeodomain Proteins
- Lateral Ventricles
- Mice, Inbred C57BL
- Microtubule-Associated Proteins
- Neurogenesis
- Neuropeptides
- Olfactory Bulb
- Oligodendroglia
- Pre-B-Cell Leukemia Transcription Factor 1
- Protein Binding
- Proto-Oncogene Proteins
- Stem Cells
- Transcription Factors
- Tyrosine 3-Monooxygenase
Keywords
- Adult neurogenesis
- Cell fate specification
- Doublecortin
- Pioneer factor
- Subventricular zone
- TALE-homeodomain protein
Expression levels of genes encoding specific transcription factors and other functionally important proteins vary upon aging of pancreatic and bronchial epithelium cell cultures. The peptides KEDW and AEDL tissue-specifically affect gene expression in pancreatic and bronchial cell cultures, respectively. It is established in this work that the DNA methylation patterns of the PDX1, PAX6, NGN3, NKX2-1, and SCGB1A1 gene promoter regions change upon aging in pancreatic and bronchial cell cultures in correlation with variations in their expression levels. Thus, stable changes in gene expression upon aging of cell cultures could be caused by changes in their promoter methylation patterns. The methylation patterns of the PAX4 gene in pancreatic cells as well as those of the FOXA1, SCGB3A2, and SFTPA1 genes in bronchial cells do not change upon aging and are unaffected by peptides, whereas their expression levels change in both cases. The promoter region of the FOXA2 gene in pancreatic cells contains a small number of methylated CpG sites, their methylation levels being affected by cell culture aging and KEDW, though without any correlation with gene expression levels. The promoter region of the FOXA2 gene is completely unmethylated in bronchial cells irrespective of cell culture age and AEDL action. Changes in promoter methylation might be the cause of age- and peptide-induced variations in expression levels of the PDX1, PAX6, and NGN3 genes in pancreatic cells and NKX2-1 and SCGB1A1 genes in bronchial cells. Expression levels of the PAX4 and FOXA2 genes in pancreatic cells and FOXA1, FOXA2, SCGB3A2, and SFTPA1 genes in bronchial cells seem to be controlled by some other mechanisms.
MeSH Terms
- Aging
- Cell Line
- Cellular Senescence
- DNA Methylation
- Epigenesis, Genetic
- Gene Expression Regulation
- Humans
- Peptides
- Promoter Regions, Genetic