| First Author | Yang YP | Year | 2017 |
| Journal | Development | Volume | 144 |
| Issue | 2 | Pages | 248-257 |
| PubMed ID | 27993987 | Mgi Jnum | J:238418 |
| Mgi Id | MGI:5819307 | Doi | 10.1242/dev.143123 |
| Citation | Yang YP, et al. (2017) The mammal-specific Pdx1 Area II enhancer has multiple essential functions in early endocrine cell specification and postnatal beta-cell maturation. Development 144(2):248-257 |
| abstractText | The transcription factor Pdx1 is required for multiple aspects of pancreatic organogenesis. It remains unclear to what extent Pdx1 expression and function depend upon trans-activation through 5' conserved cis-regulatory regions and, in particular, whether the mammal-specific Area II (-2139 to -1958 bp) affects minor or major aspects of organogenesis. We show that Area II is a primary effector of endocrine-selective transcription in epithelial multipotent cells, nascent endocrine progenitors, and differentiating and mature beta cells in vivo Pdx1DeltaAREAII/- mice exhibit a massive reduction in endocrine progenitor cells and progeny hormone-producing cells, indicating that Area II activity is fundamental to mounting an effective endocrine lineage-specification program within the multipotent cell population. Creating an Area II-deleted state within already specified Neurog3-expressing endocrine progenitor cells increased the proportion of glucagon+ alpha relative to insulin+ beta cells, associated with the transcriptional and epigenetic derepression of the alpha-cell-determining Arx gene in endocrine progenitors. There were also glucagon and insulin co-expressing cells, and beta cells that were incapable of maturation. Creating the Pdx1DeltaAREAII state after cells entered an insulin-expressing stage led to immature and dysfunctional islet beta cells carrying abnormal chromatin marking in vital beta-cell-associated genes. Therefore, trans-regulatory integration through Area II mediates a surprisingly extensive range of progenitor and beta-cell-specific Pdx1 functions. |
