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Gene Review

HAND2  -  heart and neural crest derivatives...

Homo sapiens

Synonyms: BHLHA26, Class A basic helix-loop-helix protein 26, DHAND, DHAND2, Deciduum, heart, autonomic nervous system and neural crest derivatives-expressed protein 2, ...
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Disease relevance of HAND2


Psychiatry related information on HAND2

  • Studying interactions, we noted that all four Id proteins could dimerize with E47 or E2-2, but not with HASH-1 or dHAND [2].

High impact information on HAND2

  • Right and left go dHAND and eHAND [3].
  • The four EF hands of the protein are arranged in a compact array that contrasts with the dumbbell shape of calmodulin and troponin C. A calcium ion is bound to EF hand 3, while EF hand 2 can bind samarium but not calcium in this crystal form [4].
  • Using the zebrafish hand2 deletion mutant hands off, we have now investigated the physiological role of hand2 in the development of sympathetic ganglia [5].
  • Hand2 overexpression experiments and the analysis of its function at the Dbh promotor implicated Hand2 in the control of noradrenergic gene expression [5].
  • Our data suggest a new role for Tbx3 in positioning the limb along the main body axis through a genetic interplay between dHand and Gli3 [6].

Biological context of HAND2

  • Noradrenergic neuronal identity and differentiation are controlled by cascades of transcription factors acting downstream of BMP4, including the basic helix-loop-helix DNA binding protein HAND2 and the homeodomain factor Phox2a [7].
  • Using transient transfection of P19 or NT-2 cells, HAND2 is shown to synergistically enhance Phox2a-driven transcriptional activity at the DBH promoter, an effect that is enhanced by cAMP [7].
  • We examined the conserved chromosomal locations for phenotypes that involve development of heart, face, and limb structures that are affected by HAND2 [8].
  • We used differential display analysis to identify 33 putative HAND2-regulated ESTs that are differentially expressed in Hand2(-/-) vs wild-type mice [8].
  • The amino acid sequence includes an amino-terminal polyalanine repeat which is precisely conserved in the rat HAND2 gene [9].

Anatomical context of HAND2

  • Functional analysis has shown that HAND2 is involved in development of the branchial arches, heart, limb, vasculature, and nervous system [10].
  • GDNF failed to induce consistent expression of transcripts encoding HAND2 in neural crest cells but did support a modest increase in HAND2 expression in gut-derived crest cells obtained from the esophagus and colon [11].
  • The basic helix-loop-helix transcription factors, HAND2 and HAND1, are expressed in the gastrointestinal tract, but neither the growth factors that induce their expression nor the cell types that express them in the gut are known [11].
  • Using in situ hybridization combined with immunostaining using cell type-specific antigens, we demonstrate that transcripts encoding HAND2 are expressed in neurons of both the myenteric and submucosal ganglia [11].
  • We show that transcripts encoding HAND2 are expressed in all segments of the developing gut while those encoding HAND1 are confined to the small intestine and colon [11].

Associations of HAND2 with chemical compounds

  • HAND2 synergistically enhances transcription of dopamine-beta-hydroxylase in the presence of Phox2a [7].
  • Our data suggest that HAND2 regulates cell type-specific expression of norepinephrine in concert with Phox2a by a novel mechanism [7].
  • Moreover, the bHLH domain of dHAND directly interacted with the CH3 domain of p300 suggesting the existence of a higher order complex between GATA4, dHAND, and p300 [12].
  • Further studies revealed that pretreatment with 10 microM BQ-123, a selective endothelin-1 receptor (ETAR) antagonist, for 2 h can significantly counteract the inhibition of 5 microM atRA treatment for 2 h of dHAND mRNA and protein expression [13].
  • Regulation of dHAND protein expression by all-trans retinoic acid through ET-1/ETAR signaling in H9c2 cells [13].

Physical interactions of HAND2

  • Using chromatin immunoprecipitation (ChIP) analysis in H9c2 cells we show that dHAND interact with MEF2C to form protein complex and bind A/T sequence in promoter of ANP [14].
  • Arix coprecipitated with antisera directed against recombinant dHAND, demonstrating direct protein-protein interactions [15].

Other interactions of HAND2

  • The bHLH factors HAND1 and HAND2 are required for heart, vascular, neuronal, limb, and extraembryonic development [16].
  • Surprisingly, the BAC clone RP11-56H7 that contains NEBL, an apparent downstream gene of the cardiogenic transcription factor HAND2 previously shown to be deleted in the patients with DiGeorge 2 syndrome and 10p13 deletion, was deleted in our patient with 10p12.1-p12.31 deletion [17].
  • The related HAND2 protein can also synergize with MEF2 [18].
  • We have examined the interaction of HAND2 and Phox2a at the DBH promoter [7].
  • Cooperative activation of atrial naturetic peptide promoter by dHAND and MEF2C [14].

Analytical, diagnostic and therapeutic context of HAND2


  1. HAND1 and HAND2 are expressed in the adult-rodent heart and are modulated during cardiac hypertrophy. Thattaliyath, B.D., Livi, C.B., Steinhelper, M.E., Toney, G.M., Firulli, A.B. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  2. Modulation of basic helix-loop-helix transcription complex formation by Id proteins during neuronal differentiation. Jögi, A., Persson, P., Grynfeld, A., Påhlman, S., Axelson, H. J. Biol. Chem. (2002) [Pubmed]
  3. Right and left go dHAND and eHAND. Overbeek, P.A. Nat. Genet. (1997) [Pubmed]
  4. Three-dimensional structure of recoverin, a calcium sensor in vision. Flaherty, K.M., Zozulya, S., Stryer, L., McKay, D.B. Cell (1993) [Pubmed]
  5. The bHLH transcription factor hand2 is essential for noradrenergic differentiation of sympathetic neurons. Lucas, M.E., M??ller, F., R??diger, R., Henion, P.D., Rohrer, H. Development (2006) [Pubmed]
  6. Tbx3 can alter limb position along the rostrocaudal axis of the developing embryo. Rallis, C., Del Buono, J., Logan, M.P. Development (2005) [Pubmed]
  7. HAND2 synergistically enhances transcription of dopamine-beta-hydroxylase in the presence of Phox2a. Xu, H., Firulli, A.B., Zhang, X., Howard, M.J. Dev. Biol. (2003) [Pubmed]
  8. Genetic and comparative mapping of genes dysregulated in mouse hearts lacking the Hand2 transcription factor gene. Villanueva, M.P., Aiyer, A.R., Muller, S., Pletcher, M.T., Liu, X., Emanuel, B., Srivastava, D., Reeves, R.H. Genomics (2002) [Pubmed]
  9. Molecular cloning of the human HAND2 gene. Russell, M.W., Kemp, P., Wang, L., Brody, L.C., Izumo, S. Biochim. Biophys. Acta (1998) [Pubmed]
  10. The basic helix-loop-helix factor, HAND2, functions as a transcriptional activator by binding to E-boxes as a heterodimer. Dai, Y.S., Cserjesi, P. J. Biol. Chem. (2002) [Pubmed]
  11. Transcripts encoding HAND genes are differentially expressed and regulated by BMP4 and GDNF in developing avian gut. Wu, X., Howard, M.J. Gene Expr. (2002) [Pubmed]
  12. The transcription factors GATA4 and dHAND physically interact to synergistically activate cardiac gene expression through a p300-dependent mechanism. Dai, Y.S., Cserjesi, P., Markham, B.E., Molkentin, J.D. J. Biol. Chem. (2002) [Pubmed]
  13. Regulation of dHAND protein expression by all-trans retinoic acid through ET-1/ETAR signaling in H9c2 cells. Li, W., Li, Y. J. Cell. Biochem. (2006) [Pubmed]
  14. Cooperative activation of atrial naturetic peptide promoter by dHAND and MEF2C. Zang, M.X., Li, Y., Xue, L.X., Jia, H.T., Jing, H. J. Cell. Biochem. (2004) [Pubmed]
  15. The interaction between dHAND and Arix at the dopamine beta-hydroxylase promoter region is independent of direct dHAND binding to DNA. Rychlik, J.L., Gerbasi, V., Lewis, E.J. J. Biol. Chem. (2003) [Pubmed]
  16. PKA, PKC, and the protein phosphatase 2A influence HAND factor function: a mechanism for tissue-specific transcriptional regulation. Firulli, B.A., Howard, M.J., McDaid, J.R., McIlreavey, L., Dionne, K.M., Centonze, V.E., Cserjesi, P., Virshup, D.M., Firulli, A.B. Mol. Cell (2003) [Pubmed]
  17. Interstitial deletion of 10p and atrial septal defect in DiGeorge 2 syndrome. Yatsenko, S.A., Yatsenko, A.N., Szigeti, K., Craigen, W.J., Stankiewicz, P., Cheung, S.W., Lupski, J.R. Clin. Genet. (2004) [Pubmed]
  18. MEF2-dependent recruitment of the HAND1 transcription factor results in synergistic activation of target promoters. Morin, S., Pozzulo, G., Robitaille, L., Cross, J., Nemer, M. J. Biol. Chem. (2005) [Pubmed]
  19. Phox2 and dHAND transcription factors select shared and unique target genes in the noradrenergic cell type. Rychlik, J.L., Hsieh, M., Eiden, L.E., Lewis, E.J. J. Mol. Neurosci. (2005) [Pubmed]
  20. Human eHAND, but not dHAND, is down-regulated in cardiomyopathies. Natarajan, A., Yamagishi, H., Ahmad, F., Li, D., Roberts, R., Matsuoka, R., Hill, S., Srivastava, D. J. Mol. Cell. Cardiol. (2001) [Pubmed]
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