Heart- and neural crest derivatives-expressed protein 1 is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
that in humans is encoded by the ''HAND1''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
.
A member of the HAND subclass of
basic Helix-loop-helix (bHLH) transcription factors, the Heart and neural crest-derived transcript-1 (''HAND1)'' gene is vital for the development and differentiation of three distinct embryological lineages including the cardiac muscle cells of the heart, trophoblast of the placenta, and yolk sac vasculogenesis.
Most highly related to
twist-like bHLH genes in amino acid identity and embryonic expression, HAND1 can form homo- and heterodimer combinations with multiple bHLH partners, mediating transcriptional activity in the nucleus.
Function
The protein encoded by this gene belongs to the basic helix-loop-helix family of transcription factors. This gene product is one of two closely related family members, the HAND proteins are expressed within the developing ventricular chambers, cardiac neural crest, endocardium (HAND2 only) and epicardium (HAND2 only). HAND1 is expressed with myocardium of the primary heart field and plays an essential but poorly understood role in cardiac morphogenesis.
HAND1 works jointly with HAND2 in cardiac development of embryos based on a crucial HAND gene dosage system. If HAND1 is over or under expressed then morphological abnormalities can form; most notable are cleft lips and palates. Expression was modeled with a knock-in of phosphorylation to turn on and off gene expression which induced the craniofacial abnormalities.
Knock-out experimentation on mice caused death and severe cardiac malformations such as failed cardiac looping, impaired ventricular development and defective chamber septation. This aids in the implication that HAND1 expression is a factor to patients with congenital heart disease.
However, a lack of HAND1 in the distal regions of the Neural Crest has no effect on cranial feature formation.
Mutation of HAND1 has been shown to hinder the effect of GATA4, another vital cardiac transcription factor, and is associated with congenital heart disease.
The lack of HAND1 detection in the developing embryo leads to many of the structural defects that causes heart disease and facial deformities while the dosage of HAND1 relates to the severity of these maladies.
HAND factors function in the formation of the right ventricle, left ventricle, aortic arch arteries, epicardium, and endocardium implicating them as mediators of congenital heart disease. In addition, HAND1 is uniquely expressed in trophoblasts and is essential for early trophoblast differentiation.
Cardiac morphogenesis
In the third week of fetal development the rudimentary heart (bilaterally symmetrical cardiac tube) undergoes a characteristic dextral looping, forming an asymmetrical structure with bulges that represent the incipient ventricular and atrial chambers of the heart.
Arising from cells derived from the primary heart field in the cardiac crescent, ''HAND1'' goes from being expressed on both sides of the heart tube to the ventral surface of the caudal heart segment and the aortic sac, then being restricted to the outer curvature of the left ventricle in the looped heart.
In conjunction with ''
HAND2
Heart- and neural crest derivatives-expressed protein 2 is a protein that in humans is encoded by the ''HAND2'' gene.
Function
The protein encoded by this gene belongs to the basic helix-loop-helix family of transcription factors. This gene p ...
'' (a fellow bHLH transcription factor), complementary and overlapping expression patterns are thought to play a role in interpreting asymmetrical signals in the developing heart which leads to the characteristic looping.
The two are implemented in cardiac development of embryos based on a crucial HAND gene dosage system. If ''HAND1'' is over or under expressed then morphological abnormalities can form; most notable are cleft lips and palates. Expression was modeled with a knock-in of phosphorylation to turn on and off gene expression which induced the craniofacial abnormalities.
''HAND1'' mutants also appear to develop a spectrum of cardiac abnormalities, as demonstrated in knock-out experimentation in the mouse model, where ''HAND1''-null mice displayed defects in the ventral septum, malformation of the AV valve, hypoplastic ventricles, and outflow tract abnormalities.
In humans, evidence of a frameshift mutation in the bHLH domain of ''HAND1'' has been correlated with hypoplastic left heart syndrome (a serious form 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 ...
where the left side of the heart is severely underdeveloped), aiding in the implication that ''HAND1'' expression is a factor to patients with the disease.
However, a lack of ''HAND1'' in the distal regions of the Neural Crest has no effect on cranial feature formation.
Mutation of ''HAND1'' has been shown to hinder the effect of GATA4, another vital cardiac transcription factor, and is associated with congenital heart disease.
The lack of ''HAND1'' detection in the developing embryo leads to many of the structural defects that causes heart disease and facial deformities while the dosage of ''HAND1'' relates to the severity of these maladies.
Trophoblast differentiation
In addition, ''HAND1'' is uniquely expressed in
trophoblast
The trophoblast (from Greek : to feed; and : germinator) is the outer layer of cells of the blastocyst. Trophoblasts are present four days after fertilization in humans. They provide nutrients to the embryo and develop into a large part of the pl ...
s and is essential for early trophoblast giant cell differentiation.
Trophoblast giant cells are necessary in order for placental development to proceed, participating in vital processes such as blastocyst implantation, remodeling of the maternal decidua, and secretion of hormones.
The importance of this relationship is demonstrated in ''HAND1''-null mutant mice, which display significant abnormalities in trophoblast development, such as a reduced ectoplacental cone, thin parietal yolk sac, and reduced density of trophoblast giant cells.
These homozygous ''HAND1''-null mutant embryos were arrested by E7.5 of gestation, though could be saved by contribution of wild-type cells to the trophoblast.
Yolk sac vasculogenesis
Expressed in high levels in the extraembryonic membranes throughout development, ''HAND1'' also plays a functional role in vascular development of the yolk sac.
Though not strictly required for vasculogenesis, data has shown that ''HAND1'' contributes to the fine-tuning of the vasculogenic response in the yolk sac, recruiting smooth muscle cells to the endothelial network in order to refine the primitive endothelial plexus to a functional vascular system.
This relationship has been demonstrated in the ''HAND1''-null mouse model, where embryos lacking the ''HAND1'' gene had a yolk sac vasculature defect caused by lack of vasculature refinement leading to the accumulation of
hematopoietic
Haematopoiesis (, from Greek , 'blood' and 'to make'; also hematopoiesis in American English; sometimes also h(a)emopoiesis) is the formation of blood cellular components. All cellular blood components are derived from haematopoietic stem cells. ...
cells between the yolk sac and the amnion.
References
Further reading
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{{Transcription factors, g1
Transcription factors