Nkx2-5 Second Heart Field Target Gene Ccdc117 Regulates DNA Metabolism and Proliferation

Anthony J Horton; John Brooker; William S Streitfeld; Meaghan E Flessa; Balakrishnan Pillai; Raychel Simpson; Christopher D Clark; Monika B Gooz; Kimberly K Sutton; Ann C Foley; Kyu-Ho Lee

doi:10.1038/s41598-019-39078-5

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Nkx2-5 Second Heart Field Target Gene Ccdc117 Regulates DNA Metabolism and Proliferation

Journal article

Open access

Peer reviewed

Nkx2-5 Second Heart Field Target Gene Ccdc117 Regulates DNA Metabolism and Proliferation

Anthony J Horton, John Brooker, William S Streitfeld, Meaghan E Flessa, Balakrishnan Pillai, Raychel Simpson, Christopher D Clark, Monika B Gooz, Kimberly K Sutton, Ann C Foley, …

Scientific reports, Vol.9(1), pp.1738-1738

02/11/2019

DOI: 10.1038/s41598-019-39078-5

PMCID: PMC6370788

PMID: 30742009

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Abstract

The cardiac transcription factor Nkx2-5 is essential for normal outflow tract (OFT) and right ventricle (RV) development. Nkx2-5 null mouse embryos display severe OFT and RV hypoplasia and a single ventricle phenotype due to decreased proliferation of Second Heart Field (SHF) cells, a pool of cardiac progenitors present in anterior pharyngeal arch mesoderm at mid-gestation. However, definition of the precise role of Nkx2-5 in facilitating SHF expansion is incomplete. We have found that Nkx2-5 positively and directly regulates a novel target gene, Ccdc117, in cells of the SHF at these stages. The nuclear/mitotic spindle associated protein Ccdc117 interacts with the MIP18/MMS19 cytoplasmic iron-sulfur (FeS) cluster assembly (CIA) complex, which transfers critical FeS clusters to several key enzymes with functions in DNA repair and replication. Loss of cellular Ccdc117 expression results in reduced proliferation rates associated with a delay at the G1-S transition, decreased rates of DNA synthesis, and unresolved DNA damage. These results implicate a novel role for Nkx2-5 in the regulation of cell cycle events in the developing heart, through Ccdc117's interaction with elements of the CIA pathway and the facilitation of DNA replication during SHF expansion.

Animals

Biomarkers

Cell Proliferation

DNA - genetics

DNA - metabolism

DNA Replication

Gene Expression Regulation, Developmental

Gene Knockdown Techniques

Homeobox Protein Nkx-2.5 - metabolism

Mice

Models, Biological

Details

Title: Subtitle: Nkx2-5 Second Heart Field Target Gene Ccdc117 Regulates DNA Metabolism and Proliferation
Creators: Anthony J Horton - Medical University of South Carolina
John Brooker - Medical University of South Carolina
William S Streitfeld - Medical University of South Carolina
Meaghan E Flessa - Medical University of South Carolina
Balakrishnan Pillai - Medical University of South Carolina
Raychel Simpson - Medical University of South Carolina
Christopher D Clark - Medical University of South Carolina
Monika B Gooz - Medical University of South Carolina
Kimberly K Sutton - Medical University of South Carolina
Ann C Foley - Medical University of South Carolina
Kyu-Ho Lee - Clemson University
Resource Type: Journal article
Publication Details: Scientific reports, Vol.9(1), pp.1738-1738
DOI: 10.1038/s41598-019-39078-5
PMID: 30742009
PMCID: PMC6370788
ISSN: 2045-2322
eISSN: 2045-2322
Grant note: P20 RR016434 / NCRR NIH HHS UL1 TR001450 / NCATS NIH HHS P20 GM121342 / NIGMS NIH HHS S10 OD018113 / NIH HHS P30 CA138313 / NCI NIH HHS
Language: English
Date published: 02/11/2019
Academic Unit: Obstetrics and Gynecology
Record Identifier: 9984696762602771

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