Desmin enters the nucleus of cardiac stem cells and modulates Nkx2.5 expression by participating in transcription factor complexes that interact with the nkx2.5 gene.

Christiane Fuchs,Yassemi Capetanaki,Georg Weitzer,Sofia Nikouli,Teresa Gottschamel,Hannah Paar,Philipp Heher,Martina Schultheis,Sonja Gawlas,Julia Klammer,Mario Ivankovic

doi:10.1242/bio.014993

Christiane Fuchs, Yassemi Capetanaki + Show 9 more

Open Access

https://doi.org/10.1242/bio.014993

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Journal: Biology open	Publication Date: Jan 19, 2016
Citations: 84	License type: CC BY 3.0

Affiliation: Vienna Biocenter, Academy of Athens

Abstract

ABSTRACTThe transcription factor Nkx2.5 and the intermediate filament protein desmin are simultaneously expressed in cardiac progenitor cells during commitment of primitive mesoderm to the cardiomyogenic lineage. Up-regulation of Nkx2.5 expression by desmin suggests that desmin may contribute to cardiogenic commitment and myocardial differentiation by directly influencing the transcription of the nkx2.5 gene in cardiac progenitor cells. Here, we demonstrate that desmin activates transcription of nkx2.5 reporter genes, rescues nkx2.5 haploinsufficiency in cardiac progenitor cells, and is responsible for the proper expression of Nkx2.5 in adult cardiac side population stem cells. These effects are consistent with the temporary presence of desmin in the nuclei of differentiating cardiac progenitor cells and its physical interaction with transcription factor complexes bound to the enhancer and promoter elements of the nkx2.5 gene. These findings introduce desmin as a newly discovered and unexpected player in the regulatory network guiding cardiomyogenesis in cardiac stem cells.

Highlights

The heart is the first organ developing in mammalian embryos and has to be functional throughout life (Vincent and Buckingham, 2010)
This hypothesis is strengthened by the observation that over-expression of the muscle-specific intermediate filament (IF) protein desmin causes an up-regulation of brachyury and Nkx2.5 expression in cardiac progenitor cells (CPCs) followed by a significantly improved cardiomyogenic differentiation in embryoid bodies (EBs) (Hofner et al, 2007)
Co-transfection of 10T1/2 fibroblasts with pNKE24 and a desmin-expressing plasmid resulted in a significant decrease of the LUC activity (Fig. 1B). This inhibitory effect of desmin could be reverted by co-transfection with a desmin-specific short hairpin RNA plasmid resulting in desmin expression reduced to basal levels (Fig. S1)

Summary

Introduction

The heart is the first organ developing in mammalian embryos and has to be functional throughout life (Vincent and Buckingham, 2010). The consequences of nkx2.5 haploinsufficiency in mice (Biben et al, 2000; Jay et al, 2005) and a negative auto-regulatory Nkx2.5 feedback loop (Prall et al, 2007; Tanaka et al, 1999) suggest that fine-tuning of the Nkx2.5 expression level is critical for proper CPC specification, cardiomyogenesis, and homeostasis of the adult heart (Akazawa and Komuro, 2003) This hypothesis is strengthened by the observation that over-expression of the muscle-specific intermediate filament (IF) protein desmin causes an up-regulation of brachyury and Nkx2.5 expression in CPCs followed by a significantly improved cardiomyogenic differentiation in embryoid bodies (EBs) (Hofner et al, 2007)

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