The mammal-specific Pdx1 Area II enhancer has multiple essential functions in early endocrine cell specification and postnatal ß-cell maturation.
Development
; 144(2): 248-257, 2017 01 15.
Article
em En
| MEDLINE
| ID: mdl-27993987
ABSTRACT
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 -1958â
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 ß cells in vivo Pdx1ΔAREAII/- 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+ α relative to insulin+ ß cells, associated with the transcriptional and epigenetic derepression of the α-cell-determining Arx gene in endocrine progenitors. There were also glucagon and insulin co-expressing cells, and ß cells that were incapable of maturation. Creating the Pdx1ΔAREAII state after cells entered an insulin-expressing stage led to immature and dysfunctional islet ß cells carrying abnormal chromatin marking in vital ß-cell-associated genes. Therefore, trans-regulatory integration through Area II mediates a surprisingly extensive range of progenitor and ß-cell-specific Pdx1 functions.
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Base de dados:
MEDLINE
Assunto principal:
Diferenciação Celular
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Transativadores
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Ilhotas Pancreáticas
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Elementos Facilitadores Genéticos
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Proteínas de Homeodomínio
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Células Secretoras de Insulina
Limite:
Animals
Idioma:
En
Revista:
Development
Assunto da revista:
BIOLOGIA
/
EMBRIOLOGIA
Ano de publicação:
2017
Tipo de documento:
Article