HAND1
Identifiers
AliasesHAND1, Hxt, Thing1, bHLHa27, eHand, heart and neural crest derivatives expressed 1
External IDsOMIM: 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 MbChr 11: 57.72 – 57.72 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/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]

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 with 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 with 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]

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.

Further reading

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