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 |
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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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