TBX20 (gene) is a member of the T-box family that encodes the transcription factor TBX20. Studies in mouse, human and fruitfly have shown that this gene is essential for early heart development, [5] [6] [7] [8] adult heart function [9] and yolk sac vasculature remodeling [7] and has been associated with congenital heart diseases. [10] [11] [12] Tbx20 was also shown to be required for migration of hindbrain motor neurons and in facial neurons was proposed to be a positive regulator of the non-canonical Wnt signaling pathway.
Tbx20 is a transcription factor that is essential for proper heart development in a growing fetus. Any mutations in this gene can result in various forms of congenital heart disease. One of the more serious examples is the presence of a septal defect. The interatrial septum is a piece of tissue that separates the left and right atria of the heart, which contain oxygenated and deoxygenated blood, respectively. In Tbx20 mutants, this divider does not form and results in deoxygenated blood flowing into the left atrium then left ventricle, which ships the blood to the organs and muscles. Since deoxygenated blood should not be delivered to the tissues, the result is cyanosis, or a bluish skin discoloration stemming from low oxygen concentration. Proper function of Tbx20 is essential because it controls other genes that regulate cardiomyocyte proliferation, such as Tbx2 and N-myc1. Cardiomyocytes are the basis for the correct architectural scheme of the heart, and if defects arise in these structures, proper heart development is likely unattainable. [13]
Tbx20 knockout mouse embryos die at around or before E10.5 with hypoplastic hearts. [5] [6] [7] [8]
This gene has been implicated in coordinating cardiac proliferation, regional specification [5] and formation of the cardiac chamber [6] [7] [8] Congenital heart diseases involving TBX20 include defects in septation, chamber growth and valvulogenesis [10] [11] and increased Tbx20 expression was shown to cause congenital atrial septal defects, patent foramen ovale and cardiac valve defects. [12]
In the fruitfly, knock-down of mid (midline), Drosophila's Tbx20 homolog gene, led to slower heart rate, arrythmias and abnormal myofibrillar architecture. [9] Heterozygous Tbx20 knockout adult mice displayed left ventricle dilation, decreased wall thickness and contractile abnormalities. [7] Homozygous conditional cardiomyocyte Tbx20 knockout adult mice died within 15 days after knockout induction. Mice hearts presented with dilated cardiomyopathy and contraction-related dysfunctions such as abnormal atrioventricular conduction, slower heart rate, altered ventricular depolarization/repolarization and arrhythmias. [14]
Transcription factors GATA4 and NKX2-5 have been shown to physically interact with TBX20 and enhance gene expression. [7]
Tbx2 was shown to be directly repressed by Tbx20 in the myocardium. [5] [7] Analysis of data from genome-wide chromatin immunoprecipitation against TBX20 tagged with green fluorescent protein in adult (6–8 weeks) mouse whole heart, coupled with analysis of genes differentially expressed upon loss of Tbx20, identified hundreds of putative TBX20 direct targets. [14] [15]
In the field of molecular biology, myocyte enhancer factor-2 (Mef2) proteins are a family of transcription factors which through control of gene expression are important regulators of cellular differentiation and consequently play a critical role in embryonic development. In adult organisms, Mef2 proteins mediate the stress response in some tissues. Mef2 proteins contain both MADS-box and Mef2 DNA-binding domains.
Transcription factor GATA-4 is a protein that in humans is encoded by the GATA4 gene.
Paired box gene 8, also known as PAX8, is a protein which in humans is encoded by the PAX8 gene.
Paired-like homeodomain transcription factor 2 also known as pituitary homeobox 2 is a protein that in humans is encoded by the PITX2 gene.
Homeobox protein Nkx-2.5 is a protein that in humans is encoded by the NKX2-5 gene.
Transcription factor GATA-6, also known as GATA-binding factor 6 (GATA6), is protein that in humans is encoded by the GATA6 gene. The gene product preferentially binds (A/T/C)GAT(A/T)(A) of the consensus binding sequence.
T-box transcription factor TBX5, is a protein that in humans is encoded by the TBX5 gene. Abnormalities in the TBX5 gene can result in altered limb development, Holt-Oram syndrome, Tetra-amelia syndrome, and cardiac and skeletal problems.
Insulin gene enhancer protein ISL-1 is a protein that in humans is encoded by the ISL1 gene.
T-box transcription factor TBX3 is a protein that in humans is encoded by the TBX3 gene.
Hairy/enhancer-of-split related with YRPW motif protein 2 (HEY2) also known as cardiovascular helix-loop-helix factor 1 (CHF1) is a protein that in humans is encoded by the HEY2 gene.
Homeobox protein OTX2 is a protein that in humans is encoded by the OTX2 gene.
T-box transcription factor 2 Tbx2 is a transcription factor that is encoded by the Tbx2 gene on chromosome 17q21-22 in humans. This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. Tbx2 and Tbx3 are the only T-box transcription factors that act as transcriptional repressors rather than transcriptional activators, and are closely related in terms of development and tumorigenesis. This gene plays a significant role in embryonic and fetal development through control of gene expression, and also has implications in various cancers. Tbx2 is associated with numerous signaling pathways, BMP, TGFβ, Wnt, and FGF, which allow for patterning and proliferation during organogenesis in fetal development.
ZIC3 is a member of the Zinc finger of the cerebellum (ZIC) protein family.
Heart- and neural crest derivatives-expressed protein 1 is a protein that in humans is encoded by the HAND1 gene.
Heart- and neural crest derivatives-expressed protein 2 is a protein that in humans is encoded by the HAND2 gene.
Zinc finger protein ZFPM2, i.e. zinc finger protein, FOG family member 2, but also termed Friend of GATA2, Friend of GATA-2, FOG2, or FOG-2, is a protein that in humans is encoded by the ZFPM2 and in mice by the Zfpm2 gene.
Aldehyde dehydrogenase 1 family, member A2, also known as ALDH1A2 or retinaldehyde dehydrogenase 2 (RALDH2), is an enzyme that in humans is encoded by the ALDH1A2 gene.
Protein Jumonji is a protein that in humans is encoded by the JARID2 gene. JARID2 is a member of the alpha-ketoglutarate-dependent hydroxylase superfamily.
Neural crest cells are multipotent cells required for the development of cells, tissues and organ systems. A subpopulation of neural crest cells are the cardiac neural crest complex. This complex refers to the cells found amongst the midotic placode and somite 3 destined to undergo epithelial-mesenchymal transformation and migration to the heart via pharyngeal arches 3, 4 and 6.
tinman, or tin is an Nk2-homeobox containing transcription factor first isolated in Drosophila flies. The human homolog is the Nkx2-5 gene. tinman is expressed in the precardiac mesoderm and is responsible for the differentiation, proliferation, and specification of cardiac progenitor cells. This gene is named after the character Tin Woodman who lacks a heart, as flies with nonfunctional tinman genes have cardiac deformities.