HAND1

Last updated
HAND1
Identifiers
Aliases HAND1 , Hxt, Thing1, bHLHa27, eHand, heart and neural crest derivatives expressed 1
External IDs OMIM: 602406 MGI: 103577 HomoloGene: 3545 GeneCards: HAND1
Orthologs
SpeciesHumanMouse
Entrez

9421

15110

Ensembl

ENSG00000113196

ENSMUSG00000037335

UniProt

O96004

Q64279

RefSeq (mRNA)

NM_004821

NM_008213

RefSeq (protein)

NP_004812

NP_032239

Location (UCSC) Chr 5: 154.47 – 154.48 Mb Chr 11: 57.83 – 57.83 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Heart- and neural crest derivatives-expressed protein 1 is a protein that in humans is encoded by the HAND1 gene. [5] [6] [7]

Contents

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. [8] [9] 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. [9] [10]

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. [11] 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 suffering from congenital heart disease. [12] However, a lack of HAND1 in the distal regions of the Neural Crest has no effect on cranial feature formation. [11] Mutation of HAND1 has been shown to hinder the effect of GATA4, another vital cardiac transcription factor, and is associated with congenital heart disease. [13] 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. [11]

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. [7]

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. [14] 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. [14] [15] [16] In conjunction with HAND2 (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. [14] [17] 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. [11]

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. [17] [18] 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 where the left side of the heart is severely underdeveloped), aiding in the implication that HAND1 expression is a factor to patients suffering from the disease. [12] [19]

However, a lack of HAND1 in the distal regions of the Neural Crest has no effect on cranial feature formation. [11] Mutation of HAND1 has been shown to hinder the effect of GATA4, another vital cardiac transcription factor, and is associated with congenital heart disease. [13] 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. [11]

Trophoblast differentiation

In addition, HAND1 is uniquely expressed in trophoblasts and is essential for early trophoblast giant cell differentiation. [20] 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. [20] 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. [21] 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. [21]

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. [22] 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. [22] [9] 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 cells between the yolk sac and the amnion. [22]

Related Research Articles

Basic helix–loop–helix Protein structural motif

A basic helix–loop–helix (bHLH) is a protein structural motif that characterizes one of the largest families of dimerizing transcription factors.

Inhibitor of DNA-binding/differentiation proteins, also known as ID proteins comprise a family of proteins that heterodimerize with basic helix-loop-helix (bHLH) transcription factors to inhibit DNA binding of bHLH proteins. ID proteins also contain the HLH-dimerization domain but lack the basic DNA-binding domain and thus regulate bHLH transcription factors when they heterodimerize with bHLH proteins. The first helix-loop-helix proteins identified were named E-proteins because they bind to Ephrussi-box (E-box) sequences. In normal development, E proteins form dimers with other bHLH transcription factors, allowing transcription to occur. However, in cancerous phenotypes, ID proteins can regulate transcription by binding E proteins, so no dimers can be formed and transcription is inactive. E proteins are members of the class I bHLH family and form dimers with bHLH proteins from class II to regulate transcription. Four ID proteins exist in humans: ID1, ID2, ID3, and ID4. The ID homologue gene in Drosophila is called extramacrochaetae (EMC) and encodes a transcription factor of the helix-loop-helix family that lacks a DNA binding domain. EMC regulates cell proliferation, formation of organs like the midgut, and wing development. ID proteins could be potential targets for systemic cancer therapies without inhibiting the functioning of most normal cells because they are highly expressed in embryonic stem cells, but not in differentiated adult cells. Evidence suggests that ID proteins are overexpressed in many types of cancer. For example, ID1 is overexpressed in pancreatic, breast, and prostate cancers. ID2 is upregulated in neuroblastoma, Ewing’s sarcoma, and squamous cell carcinoma of the head and neck.

Myogenesis Formation of muscular tissue, particularly during embryonic development

Myogenesis is the formation of skeletal muscular tissue, particularly during embryonic development.

Myogenin

Myogenin, is a transcriptional activator encoded by the MYOG gene. Myogenin is a muscle-specific basic-helix-loop-helix (bHLH) transcription factor involved in the coordination of skeletal muscle development or myogenesis and repair. Myogenin is a member of the MyoD family of transcription factors, which also includes MyoD, Myf5, and MRF4.

Mef2

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.

The gene extramachrochaetae (emc) is a Drosophila melanogaster gene that codes for the Emc protein, which has a wide variety of developmental roles. It was named, as is common for Drosophila genes, after the phenotypic change caused by a mutation in the gene.

NEUROD1

Neurogenic differentiation 1 (NeuroD1), also called β2, is a transcription factor of the NeuroD-type. It is encoded by the human gene NEUROD1.

HES1

Transcription factor HES1 is a protein that is encoded by the Hes1 gene, and is the mammalian homolog of the hairy gene in Drosophila. HES1 is one of the seven members of the Hes gene family (HES1-7). Hes genes code nuclear proteins that suppress transcription.

ASCL1

Achaete-scute homolog 1 is a protein that in humans is encoded by the ASCL1 gene. Because it was discovered subsequent to studies on its homolog in Drosophila, the Achaete-scute complex, it was originally named MASH-1 for mammalian achaete scute homolog-1.

HEY2

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.

ID4 Protein-coding gene in humans

ID4 is a protein coding gene. In humans, it encodes for the protein known as DNA-binding protein inhibitor ID-4. This protein is known to be involved in the regulation of many cellular processes during both prenatal development and tumorigenesis. This is inclusive of embryonic cellular growth, senescence, cellular differentiation, apoptosis, and as an oncogene in angiogenesis.

HAND2 Protein-coding gene in the species Homo sapiens

Heart- and neural crest derivatives-expressed protein 2 is a protein that in humans is encoded by the HAND2 gene.

ATOH1

Protein atonal homolog 1 is a protein that in humans is encoded by the ATOH1 gene.

TCF21 (gene)

Transcription factor 21 (TCF21), also known as pod-1, capsuling, or epicardin, is a protein that in humans is encoded by the TCF21 gene on chromosome 6. It is ubiquitously expressed in many tissues and cell types and highly significantly expressed in lung and placenta. TCF21 is crucial for the development of a number of cell types during embryogenesis of the heart, lung, kidney, and spleen. TCF21 is also deregulated in several types of cancers, and thus known to function as a tumor suppressor. The TCF21 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.

Neurogenins are a family of bHLH transcription factors involved in specifying neuronal differentiation. It is one of many gene families related to the atonal gene in Drosophila. Other positive regulators of neuronal differentiation also expressed during early neural development include NeuroD and ASCL1.

NEUROD2

Neurogenic differentiation factor 2 is a protein that in humans is encoded by the NEUROD2 gene.

ASCL2

Achaete-scute complex homolog 2 (Drosophila), also known as ASCL2, is an imprinted human gene.

HEYL

Hairy/enhancer-of-split related with YRPW motif-like protein is a protein that in humans is encoded by the HEYL gene.

Proneural genes encode transcription factors of the basic helix-loop-helix (bHLH) class which are responsible for the development of neuroectodermal progenitor cells. Proneural genes have multiple functions in neural development. They integrate positional information and contribute to the specification of progenitor-cell identity. From the same ectodermal cell types, neural or epidermal cells can develop based on interactions between proneural and neurogenic genes. Neurogenic genes are so called because loss of function mutants show an increase number of developed neural precursors. On the other hand, proneural genes mutants fail to develop neural precursor cells.

HES7 gene

(HES7) or bHLHb37 is protein coding mammalian gene found on chromosome 17 in humans. HES7 is a member of the Hairy and Enhancer of Split families of Basic helix-loop-helix proteins. The gene product is a transcription factor and is expressed cyclically in the presomitic mesoderm as part of the Notch signalling pathway. HES7 is involved in the segmentation of somites from the presomitic mesoderm in vertebrates. The HES7 gene is self-regulated by a negative feedback loop in which the gene product can bind to its own promoter. This causes the gene to be expressed in an oscillatory manner. The HES7 protein also represses expression of Lunatic Fringe (LFNG) thereby both directly and indirectly regulating the Notch signalling pathway. Mutations in HES7 can result in deformities of the spine, ribs and heart. Spondylocostal dysostosis is a common disease caused by mutations in the HES7 gene. The inheritance pattern of Spondylocostal dysostosis is autosomal recessive.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000113196 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000037335 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Russell MW, Baker P, Izumo S (January 1998). "Cloning, chromosomal mapping, and expression of the human eHAND gene". Mammalian Genome. 8 (11): 863–5. doi:10.1007/s003359900596. hdl: 2027.42/42138 . PMID   9337404. S2CID   7799338.
  6. ↑ Knöfler M, Meinhardt G, Vasicek R, Husslein P, Egarter C (December 1998). "Molecular cloning of the human Hand1 gene/cDNA and its tissue-restricted expression in cytotrophoblastic cells and heart". Gene. 224 (1–2): 77–86. doi:10.1016/S0378-1119(98)00511-3. PMID   9931445.
  7. 1 2 "Entrez Gene: HAND1 heart and neural crest derivatives expressed 1".
  8. ↑ Firulli AB (July 2003). "A HANDful of questions: the molecular biology of the heart and neural crest derivatives (HAND)-subclass of basic helix-loop-helix transcription factors". Gene. 312: 27–40. doi:10.1016/s0378-1119(03)00669-3. PMID   12909338.
  9. 1 2 3 Smart N, Dubé KN, Riley PR (July 2010). "Identification of Thymosin β4 as an effector of Hand1-mediated vascular development". Nature Communications. 1 (4): 46. Bibcode:2010NatCo...1...46S. doi:10.1038/ncomms1041. PMC   2963826 . PMID   20975697.
  10. ↑ Asuthkar S, Gogineni VR, Rao JS, Velpula KK (May 2014). "Nuclear translocation of Hand-1 acts as a molecular switch to regulate vascular radiosensitivity in medulloblastoma tumors: the protein uPAR is a cytoplasmic sequestration factor for Hand-1". Molecular Cancer Therapeutics. 13 (5): 1309–22. doi: 10.1158/1535-7163.MCT-13-0892 . PMID   24623737.
  11. 1 2 3 4 5 6 Firulli BA, Fuchs RK, Vincentz JW, Clouthier DE, Firulli AB (August 2014). "Hand1 phosphoregulation within the distal arch neural crest is essential for craniofacial morphogenesis". Development. 141 (15): 3050–61. doi:10.1242/dev.107680. PMC   4197675 . PMID   25053435.
  12. 1 2 Reamon-Buettner SM, Ciribilli Y, Traverso I, Kuhls B, Inga A, Borlak J (October 2009). "A functional genetic study identifies HAND1 mutations in septation defects of the human heart". Human Molecular Genetics. 18 (19): 3567–78. doi: 10.1093/hmg/ddp305 . PMID   19586923.
  13. 1 2 Zhou YM, Dai XY, Qiu XB, Yuan F, Li RG, Xu YJ, Qu XK, Huang RT, Xue S, Yang YQ (July 2016). "HAND1 loss-of-function mutation associated with familial dilated cardiomyopathy". Clinical Chemistry and Laboratory Medicine. 54 (7): 1161–7. doi:10.1515/cclm-2015-0766. PMID   26581070. S2CID   22700829.
  14. 1 2 3 Carlson BM (2014). Human Embryology and Developmental Biology (5th ed.). Philadelphia, Pa.: Elsevier/Saunders. ISBN   978-1-4557-2797-1.
  15. ↑ Harvey RP (February 1999). "Seeking a regulatory roadmap for heart morphogenesis". Seminars in Cell & Developmental Biology. 10 (1): 99–107. doi:10.1006/scdb.1998.0277. PMID   10355034.
  16. ↑ Togi K, Kawamoto T, Yamauchi R, Yoshida Y, Kita T, Tanaka M (June 2004). "Role of Hand1/eHAND in the dorso-ventral patterning and interventricular septum formation in the embryonic heart". Molecular and Cellular Biology. 24 (11): 4627–35. doi:10.1128/MCB.24.11.4627-4635.2004. PMC   416422 . PMID   15143159.
  17. 1 2 McFadden DG, Barbosa AC, Richardson JA, Schneider MD, Srivastava D, Olson EN (January 2005). "The Hand1 and Hand2 transcription factors regulate expansion of the embryonic cardiac ventricles in a gene dosage-dependent manner". Development. 132 (1): 189–201. doi: 10.1242/dev.01562 . PMID   15576406.
  18. ↑ Wolf M, Basson CT (May 2010). "The molecular genetics of congenital heart disease: a review of recent developments". Current Opinion in Cardiology. 25 (3): 192–7. doi:10.1097/HCO.0b013e328337b4ce. PMC   2930935 . PMID   20186050.
  19. ↑ Reamon-Buettner SM, Ciribilli Y, Inga A, Borlak J (May 2008). "A loss-of-function mutation in the binding domain of HAND1 predicts hypoplasia of the human hearts". Human Molecular Genetics. 17 (10): 1397–405. doi: 10.1093/hmg/ddn027 . PMID   18276607.
  20. 1 2 Scott IC, Anson-Cartwright L, Riley P, Reda D, Cross JC (January 2000). "The HAND1 basic helix-loop-helix transcription factor regulates trophoblast differentiation via multiple mechanisms". Molecular and Cellular Biology. 20 (2): 530–41. doi:10.1128/MCB.20.2.530-541.2000. PMC   85124 . PMID   10611232.
  21. 1 2 Riley P, Anson-Cartwright L, Cross JC (March 1998). "The Hand1 bHLH transcription factor is essential for placentation and cardiac morphogenesis". Nature Genetics. 18 (3): 271–5. doi:10.1038/ng0398-271. PMID   9500551. S2CID   24923104.]
  22. 1 2 3 Morikawa Y, Cserjesi P (May 2004). "Extra-embryonic vasculature development is regulated by the transcription factor HAND1". Development. 131 (9): 2195–204. doi: 10.1242/dev.01091 . PMID   15073150.

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