Ablation of Nkx2-5 at mid-embryonic stage results in premature lethality and cardiac malformation

Autor: Kenneth R. Chien, Hideko Kasahara, Jonathan T. Lu, Andy Wessels, Sonisha Warren, Ryota Terada
Rok vydání: 2011
Předmět:
Heart Defects
Congenital
Male
Cardiac function curve
medicine.medical_specialty
Physiology
Heart Ventricles
Septum secundum
Gestational Age
Biology
Heart Septal Defects
Atrial
Atrial septal defects
Homeobox protein Nkx-2.5
Original Article: Spotlight on Cardiac Development
Mice
Heart Conduction System
Heart Rate
Physiology (medical)
Internal medicine
Morphogenesis
medicine
Animals
Calcium Signaling
Atrium (heart)
Ultrasonography
Homeodomain Proteins
Mice
Knockout
Analysis of Variance
Atrial Septum
Heart development
Gene Expression Regulation
Developmental
Heart
Myocardial Contraction
Tamoxifen
medicine.anatomical_structure
embryonic structures
Acetylcholinesterase
Homeobox Protein Nkx-2.5
cardiovascular system
Cardiology
Female
MYH6
Electrical conduction system of the heart
Cardiology and Cardiovascular Medicine
Transcription Factors
Zdroj: Cardiovascular Research. 91:289-299
ISSN: 1755-3245
0008-6363
DOI: 10.1093/cvr/cvr037
Popis: Aims Human congenital heart disease linked to mutations in the homeobox transcription factor, NKX2-5, is characterized by cardiac anomalies, including atrial and ventricular septal defects as well as conduction and occasional defects in contractility. In the mouse, homozygous germline deletion of Nkx2-5 gene results in death around E10.5. It is, however, not established whether Nkx2-5 is necessary for cardiac development beyond this embryonic stage. Because human NKX2-5 mutations are related to septum secundum type atrial septal defects (ASD), we hypothesized that Nkx2-5 deficiency during the processes of septum secundum formation may cause cardiac anomalies; thus, we analysed mice with tamoxifen-inducible Nkx2-5 ablation beginning at E12.5 when the septum secundum starts to develop. Methods and results Using tamoxifen-inducible Nkx2-5 gene-targeted mice, this study demonstrates that Nkx2-5 ablation beginning at E12.5 results in embryonic death by E17.5. Analysis of mutant embryos at E16.5 shows arrhythmias, contraction defects, and cardiac malformations, including ASD. Quantitative measurements using serial section histology and three-dimensional reconstruction demonstrate growth retardation of the septum secundum and enlarged foramen ovale in Nkx2-5-ablated embryos. Functional cardiac defects may be attributed to abnormal expression of transcripts critical for conduction and contraction, including cardiac voltage-gated Na+ channel pore-forming α-subunit (Nav1.5-α), gap junction protein connexin40, cardiac myosin light chain kinase, and sarcolipin within 4 days after tamoxifen injection. Conclusion Nkx2-5 is necessary for survival after the mid-embryonic stage for cardiac function and formation by regulating the expression of its downstream target genes.
Databáze: OpenAIRE
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