Pdx1 regulates pancreas tubulogenesis and E-cadherin expression.
Development
; 143(1): 101-12, 2016 Jan 01.
Article
em En
| MEDLINE
| ID: mdl-26657766
ABSTRACT
Current efforts in developing treatments for diabetes focus on in vitro generation of functional ß-cells for cell replacement therapies; however, these attempts have only been partly successful because factors involved in islet formation remain incompletely understood. The embryonic pancreas, which gives rise to ß-cells, undergoes early epithelial rearrangements, including transient stratification of an initially monolayered epithelium, followed by microlumen formation and later resolution into branches. Within the epithelium, a multipotent progenitor cell (MPC) population is specified, giving rise to three important lineages acinar, ductal and endocrine. Pdx1 is a transcription factor required for pancreas development and lineage specification; however, few Pdx1 targets that regulate pancreatogenesis have been identified. We find that pancreatic defects in Pdx1(-/-) embryos initiate at the time when the progenitor pool is specified and the epithelium should resolve into branches. Pdx1(-/-) microlumen diameters expand aberrantly, resulting in failure of epithelial tubulogenesis and ductal plexus formation. Pdx1(-/-) epithelial cell proliferation is decreased and the MPC pool is rapidly lost. We identify two conserved Pdx1 binding sites in the epithelial cadherin (E-cad, Cdh1) promoter, and show that Pdx1 directly binds and activates E-cad transcription. In addition, Pdx1 is required in vivo for maintenance of E-cad expression, actomyosin complex activity and cell shape. These findings demonstrate a novel link between regulators of epithelial architecture, specification of pancreatic cell fate and organogenesis.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Pâncreas
/
Caderinas
/
Transativadores
/
Proteínas de Homeodomínio
/
Regulação da Expressão Gênica no Desenvolvimento
/
Células Secretoras de Insulina
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Development
Assunto da revista:
BIOLOGIA
/
EMBRIOLOGIA
Ano de publicação:
2016
Tipo de documento:
Article
País de afiliação:
Estados Unidos