T-box
T-box refers to a group of transcription factors involved in embryonic limb and heart development. Every T-box protein has a relatively large DNA-binding domain, generally comprising about a third of the entire protein that is both necessary a ...
family that encodes the transcription factor TBX20. Studies in mouse, human and fruitfly have shown that this gene is essential for early heart development, adult heart function and
yolk sac
The yolk sac is a membranous sac attached to an embryo, formed by cells of the hypoblast layer of the bilaminar embryonic disc. This is alternatively called the umbilical vesicle by the Terminologia Embryologica (TE), though ''yolk sac'' is ...
vasculature
The blood circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the entire body of a human or other vertebrate. It includes the cardiovascular system, or vascular system, tha ...
remodeling and has been associated with congenital heart diseases. Tbx20 was also shown to be required for migration of
hindbrain
The hindbrain or rhombencephalon or lower brain is a developmental categorization of portions of the central nervous system in vertebrates. It includes the medulla, pons, and cerebellum. Together they support vital bodily processes. Metencephal ...
motor neurons
A motor neuron (or motoneuron or efferent neuron) is a neuron whose cell body is located in the motor cortex, brainstem or the spinal cord, and whose axon (fiber) projects to the spinal cord or outside of the spinal cord to directly or indirectly ...
and in facial neurons was proposed to be a positive regulator of the non-canonical
Wnt signaling pathway
The Wnt signaling pathways are a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors. The name Wnt is a portmanteau created from the names Wingless and Int-1. Wnt signaling ...
.
Tbx20 is a
transcription factor
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The f ...
that is essential for proper heart development in a growing
fetus
A fetus or foetus (; plural fetuses, feti, foetuses, or foeti) is the unborn offspring that develops from an animal embryo. Following embryonic development the fetal stage of development takes place. In human prenatal development, fetal dev ...
. Any mutations in this gene can result in various forms of
congenital heart disease
A congenital heart defect (CHD), also known as a congenital heart anomaly and congenital heart disease, is a defect in the structure of the heart or great vessels that is present at birth. A congenital heart defect is classed as a cardiovascular ...
. One of the more serious examples is the presence of a
septal defect
A congenital heart defect (CHD), also known as a congenital heart anomaly and congenital heart disease, is a defect in the structure of the heart or great vessels that is present at birth. A congenital heart defect is classed as a cardiovascular ...
. The
interatrial septum
The interatrial septum is the wall of tissue that separates the right and left atria of the heart.
Structure
The interatrial septum is a that lies between the left atrium and right atrium of the human heart. The interatrial septum lies at angl ...
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
A ventricle is one of two large chambers toward the bottom of the heart that collect and expel blood towards the peripheral beds within the body and lungs. The blood pumped by a ventricle is supplied by an atrium, an adjacent chamber in the uppe ...
, 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
Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle th ...
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.
Embryonic heart functions
Tbx20
knockout mouse
A knockout mouse, or knock-out mouse, is a genetically modified mouse (''Mus musculus'') in which researchers have inactivated, or " knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are importa ...
embryos
An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male spe ...
die at around or before E10.5 with
hypoplastic
Hypoplasia (from Ancient Greek :wikt:ὑπό, ὑπo- ''hypo-'' 'under' + πλάσις ''plasis'' 'formation'; adjective form ''hypoplastic'') is underdevelopment or incomplete development of a tissue or organ.fruitfly, knock-down of ''mid'' (
midline
In typography, the mean line is the imaginary line at the top of the x-height.
upright 2.0, alt=A diagram showing the line terms used in typography
Round glyphs will tend to break ( overshoot) the mean line slightly in many typefaces
A typ ...
), ''
Drosophila
''Drosophila'' () is a genus of flies, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or (less frequently) pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many speci ...
s Tbx20
homolog
In biology, homology is similarity due to shared ancestry between a pair of structures or genes in different taxa. A common example of homologous structures is the forelimbs of vertebrates, where the wings of bats and birds, the arms of prima ...
gene, led to slower heart rate, arrythmias and abnormal
myofibrillar
A myofibril (also known as a muscle fibril or sarcostyle) is a basic rod-like organelle of a muscle cell. Skeletal muscles are composed of long, tubular cells known as muscle fibers, and these cells contain many chains of myofibrils. Each myofibr ...
left ventricle
A ventricle is one of two large chambers toward the bottom of the heart that collect and expel blood towards the peripheral beds within the body and lungs. The blood pumped by a ventricle is supplied by an atrium, an adjacent chamber in the uppe ...
dilation, decreased wall thickness and contractile abnormalities.
Homozygous
Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism.
Mo ...
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
In biology, depolarization or hypopolarization is a change within a cell, during which the cell undergoes a shift in electric charge distribution, resulting in less negative charge inside the cell compared to the outside. Depolarization is ess ...
/repolarization and arrhythmias.
Known co-factors
Transcription factors
GATA4
Transcription factor GATA-4 is a protein that in humans is encoded by the ''GATA4'' gene.
Function
This gene encodes a member of the GATA family of zinc finger transcription factors. Members of this family recognize the GATA motif which is pr ...
and
NKX2-5
Homeobox protein Nkx-2.5 is a protein that in humans is encoded by the ''NKX2-5'' gene.
Function
Homeobox-containing genes play critical roles in regulating tissue-specific gene expression essential for tissue differentiation, as well as dete ...
have been shown to physically interact with TBX20 and enhance gene expression.
Known downstream gene targets
Tbx2 was shown to be directly repressed by Tbx20 in the myocardium. Analysis of data from
genome
In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding g ...
fluorescent protein Fluorescent proteins include:
* Green fluorescent protein (GFP)
* Yellow fluorescent protein
Yellow fluorescent protein (YFP) is a genetic mutant of green fluorescent protein (GFP) originally derived from the jellyfish '' Aequorea victoria''. Its ...
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.