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EMBO reports 6, 12, 1182–1187 (2005)
doi:10.1038/sj.embor.7400539
Published online: 23 September 2005
Developmental regulation of a proinsulin messenger RNA generated by intron retention
Alicia Mansilla1, Carmen López-Sánchez2, Enrique J de la Rosa1, Virginio García-Martínez2, Encarna Martínez-Salas3, Flora de Pablo1 & Catalina Hernández-Sánchez1
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1 Group of Growth Factors in Vertebrate Development, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), Ramiro de Maeztu 9, 28040 Madrid, Spain
2 Anatomía y Embriología Humana, Facultad de Medicina, Universidad de Extremadura, Apto. 108, 06080 Badajoz, Spain
3 Centro de Biología Molecular 'Severo Ochoa', CSIC-Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain
To whom correspondence should be addressed
Flora de Pablo Tel/Fax: +34 91 5349201; E-mail: fdepablo@cib.csic.es
Received 16 March 2005; Accepted 22 August 2005; Published online 23 September 2005.
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Abstract
Proinsulin gene expression regulation and function during early embryonic development differ remarkably from those found in postnatal organisms. The embryonic proinsulin protein content decreased from gastrulation to neurulation in contrast with the overall proinsulin messenger RNA increase. This is due to increasing levels of a proinsulin mRNA variant generated by intron 1 retention in the 5' untranslated region. Inclusion of intron 1 inhibited proinsulin translation almost completely without affecting nuclear export or cytoplasmic decay. The novel proinsulin mRNA isoform expression was developmentally regulated and tissue specific. The proportion of intron retention increased from gastrulation to organogenesis, was highest in the heart tube and presomitic region, and could not be detected in the pancreas. Notably, proinsulin addition induced cardiac marker gene expression in the early embryonic stages when the translationally active transcript was expressed. We propose that regulated unproductive splicing and translation is a mechanism that regulates proinsulin expression in accordance with specific requirements in developing vertebrates.
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