Homeobox protein Nkx-2.5 is a protein that in humans is encoded by the NKX2-5 gene. [5] [6] [7]
Homeobox protein Nkx-2.5 is a protein that in humans is encoded by the NKX2-5 gene. [5] [6] [7]
Homeobox-containing genes play critical roles in regulating tissue-specific gene expression essential for tissue differentiation, as well as determining the temporal and spatial patterns of development (Shiojima et al., 1995). It has been demonstrated that a Drosophila homeobox-containing gene called 'tinman' is expressed in the developing dorsal vessel and in the equivalent of the vertebrate heart. Mutations in tinman result in loss of heart formation in the embryo, suggesting that tinman is essential for Drosophila heart formation. Furthermore, abundant expression of Csx, the presumptive mouse homolog of tinman, is observed only in the heart from the time of cardiac differentiation. CSX, the human homolog of murine Csx, has a homeodomain sequence identical to that of Csx and is expressed only in the heart, again suggesting that CSX plays an important role in human heart formation. [7] In humans, proper NKX2-5 expression is essential for the development of atrial, ventricular, and conotruncal septation, atrioventricular (AV) valve formation, and maintenance of AV conduction. Mutations in expression are associated with congenital heart disease (CHD) and related ailments. Patients with NKX2-5 mutations commonly present AV conduction block and atrial septal defects (ASD). Recently, postnatal roles of cardiac transcription factors have been extensively investigated. Consistent with the direct transactivation of numerous cardiac genes reactivated in response to hypertrophic stimulation, cardiac transcription factors are profoundly involved in the generation of cardiac hypertrophy or in cardioprotection from cytotoxic stress in the adult heart. The NKX2-5 transcription factor may help myocytes endure cytotoxic stress, however further exploration in this field is required. [8]
NK-2 homeobox genes are a family of genes that encode for numerous transcription factors that go on to aid in the development of many structures including the thyroid, colon, and heart. [9] [10] [11] Of the NK-2 genes, NKX2-5 transcription factor is mostly involved in cardiac development and defects with this gene can lead to congenital heart defects including, but not limited to atrial septal defects. [12] NKX2-5 is expressed in precursor cardiac cells and this expression is necessary in order to lead to proper cardiac development. [13] In NKX2-5 gene knock out mice, subjects were found to have induced congenital heart defects by leading to differentially expressed genes. [14] In the case of loss of function of NKX2-5, test subjects developed increased heart rate and decreased variability in heart rate. [15] This discovery indicates that NKX2-5 is necessary for proper cardiac formatting as well as proper cardiac function after formatting. NKX2-5 has also been shown to bind to the promoter of FGF-16 and regulate its expression. This finding suggests that NKX2-5 is implicated in cardiac injury via cytotoxic effects. [16]
During embryogenesis, NKX2-5 is expressed in early cardiac mesoderm cells throughout the left ventricle and atrial chambers. In early cardiogenesis, cardiac precursor cells from the cardiac crescent congregate along the ventral midline of the developing embryo and form the linear heart tube. In Nkx2-5 knock out mice, cardiac development halts at the linear heart tube stage and looping morphogenesis disrupted.
NKX2-5 has been shown to interact with GATA4 [17] [18] [19] and TBX5. [17] [20] NKX2-5 is a transcription factor that regulates heart development from the Cardiac Crescent of the splanchnic mesoderm in humans. [21] NKX2-5 is dependent upon the JAK-STAT pathway [22] and works along with MEF2, HAND1, and HAND2 transcription factors to direct heart looping during early heart development. NKX2-5 in vertebrates is equivalent to the ‘tinman’ gene in Drosophila and directly activates the MEF2 gene to control cardiomyocyte differentiation. NKX2-5 operates in a positive feedback loop with GATA transcription factors to regulate cardiomyocyte formation. NKX2-5 influences HAND1 and HAND2 transcription factors that control the essential asymmetrical development of the heart's ventricles. The gene has been shown to play a role in the heart's conduction system, postnatally. [23] NKX2-5 is also involved in the intrinsic mechanisms that decide ventricle and atrial cellular fate. During ventricular chamber formation, NKX2-5 and NKX2-7 are required to maintain cardiomyocyte cellular identity. Repression of either gene results in the differentiating cardiomyocytes to move towards atrial chamber identity. The NKX2-5 mutation has also been associated with preeclampsia; though research is still being conducting in this area. [24]
A homeobox is a DNA sequence, around 180 base pairs long, that regulates large-scale anatomical features in the early stages of embryonic development. Mutations in a homeobox may change large-scale anatomical features of the full-grown organism.
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 and sufficient for sequence-specific DNA binding. All members of the T-box gene family bind to the "T-box", a DNA consensus sequence of TCACACCT.
Transcription factor GATA-4 is a protein that in humans is encoded by the GATA4 gene.
Homeobox protein Nkx-3.1, also known as NKX3-1, NKX3, BAPX2, NKX3A and NKX3.1 is a protein that in humans is encoded by the NKX3-1 gene located on chromosome 8p. NKX3-1 is a prostatic tumor suppressor gene.
NK2 homeobox 1 (NKX2-1), also known as thyroid transcription factor 1 (TTF-1), is a protein which in humans is encoded by the NKX2-1 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.
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.
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.
Heart- and neural crest derivatives-expressed protein 2 is a protein that in humans is encoded by the HAND2 gene.
Ankyrin repeat domain-containing protein 1, or Cardiac ankyrin repeat protein is a protein that in humans is encoded by the ANKRD1 gene also known as CARP. CARP is highly expressed in cardiac and skeletal muscle, and is a transcription factor involved in development and under conditions of stress. CARP has been implicated in several diseases, including dilated cardiomyopathy, hypertrophic cardiomyopathy, and several skeletal muscle myopathies.
Homeobox protein Nkx-2.2 is a protein that in humans is encoded by the NKX2-2 gene.
Homeobox protein Nkx-2.3 is a protein that in humans is encoded by the NKX2-3 gene.
NK3 homeobox 2 also known as NKX3-2 is a human gene. It is a homolog of bagpipe (bap) in Drosophila and therefore also known as Bapx1. The protein encoded by this gene is a homeodomain containing transcription factor.
Homeobox protein Nkx-6.1 is a protein that in humans is encoded by the NKX6-1 gene.
Homeobox protein Nkx-6.2 is a protein that in humans is encoded by the NKX6-2 gene.
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, adult heart function and yolk sac vasculature remodeling and has been associated with congenital heart diseases. 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.
P19 cells is an embryonic carcinoma cell line derived from an embryo-derived teratocarcinoma in mice. The cell line is pluripotent and can differentiate into cell types of all three germ layers. Also, it is the most characterized embryonic carcinoma (EC) cell line that can be induced into cardiac muscle cells and neuronal cells by different specific treatments. Indeed, exposing aggregated P19 cells to dimethyl sulfoxide (DMSO) induces differentiation into cardiac and skeletal muscle. Also, exposing P19 cells to retinoic acid (RA) can differentiate them into neuronal cells.
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.
{{cite journal}}: CS1 maint: multiple names: authors list (link)This article incorporates text from the United States National Library of Medicine, which is in the public domain.