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Gene Review

Myl4  -  myosin, light polypeptide 4

Mus musculus

Synonyms: ALC1, AMLC, ELC, ELC1a, GT1, ...
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Disease relevance of Myl4


High impact information on Myl4


Chemical compound and disease context of Myl4


Biological context of Myl4

  • Enzymatically disaggregated atrial and ventricular mouse myocytes were field-stimulated at multiple frequencies, and mechanical properties and calcium kinetics were studied by use of video edge detection and FURA 2-AM, respectively [12].
  • The cardiac tissue-restricted homeobox protein Csx/Nkx2.5 physically associates with the zinc finger protein GATA4 and cooperatively activates atrial natriuretic factor gene expression [13].
  • Transient transfection assays of mouse skeletal muscle cell lines with DNA constructs containing MLC1A promoter fragments fused to the chloramphenicol acetyltransferase (CAT) gene show that the first 630 bp of the promoter is sufficient to direct expression of the reporter gene during myotube formation [1].
  • Using a lacZ/knock-in mouse and three lines of transgenic mouse harboring various CARP promoter/lacZ reporters, we have identified distinct 5' cis regulatory elements of the gene that can direct heart segment-specific transgene expression, such as atrial versus ventricular and left versus right [14].
  • Downregulation of atrial markers during cardiac chamber morphogenesis is irreversible in murine embryos [15].

Anatomical context of Myl4

  • Electron microscopy revealed a cardiomyocyte-like ultrastructure, including typical sarcomeres, a centrally positioned nucleus, and atrial granules [16].
  • This process is complete by 10.5 d p.c. During this time, MHC alpha mRNA levels decrease in ventricular muscle cells but continue to be expressed at high levels in atrial muscle cells [17].
  • Between 7.5 and 8 d post coitum (p.c.), the newly formed cardiac tube begins to express MHC alpha, MHC beta, MLC1 atrial (MLC1A), and MLC1 ventricular (MLC1V) gene transcripts at high levels throughout the myocardium [17].
  • Mutations within the CArG box distinguish between the binding of this complex and binding of SRF; only SRF binding is directly involved in the specific regulation of the MLC1A gene in skeletal muscle cell lines [1].
  • In fetuses treated with beta-bungarotoxin and which therefore develop in the absence of functional nerve, MLC1A and MLC1F undergo normal transitions but MLC3F mRNA accumulation is significantly retarded [18].

Associations of Myl4 with chemical compounds

  • The NH2-terminal region of MLC1A/MLC1emb, thought to be involved in the actomyosin interaction, shows conservation with MLC1V but not with MLC1F suggesting a shared functional domain in these cardiac isoforms [19].
  • RESULTS: Atrial fibrillation lasting for a mean of 5.7+/-11 min was initiated in 10 of 14 WT mice in the presence of carbachol, but not in the absence of carbachol [2].
  • No significant changes in ANP or atrial BNP mRNA were found [20].
  • Reduced plasma epinephrine and corticosterone levels and adrenal medullary EGR-1 protein levels in CRH knockout versus WT mice during stress indicate that the HPA axis plays a crucial role in regulation of the PNMT gene expression in these organs.Cardiac atrial PNMT gene expression with stress is also dependent on intact HPA axis [21].
  • We hypothesize that retinoic acid provides a critical signal mediated through the RXR alpha pathway that is required to allow progression of development of the ventricular region of the heart from its early atrial-like form to the thick-walled adult ventricle [22].

Regulatory relationships of Myl4

  • Myosin light chain 1 atrial isoform (MLC1A) is expressed in pre-B cells under control of the BOB.1/OBF.1 coactivator [23].

Other interactions of Myl4

  • In contrast, the cardiac MLC1A mRNA is initially more abundant than that encoding the skeletal MLC1F isoform [24].
  • For example, in the myotome, when myosin light chain genes are initially transcribed, hybridization signal with probe for MLC1A mRNA is greater than that with probe for MLC1F transcripts, whereas the relative intensity of signal with these same probes is reversed in the hindlimb [25].
  • Among these is an "MLC-sequence" (CCTTTTATAG) common to all MLC genes, including those of chick and rat, and a "cardiac sequence" common to the mouse MLC1A, MLC1V and alpha-cardiac actin genes expressed in the heart [26].
  • Consistent with this conclusion is the observation that transcriptional induction of the endogenous MLC1A gene by BOB.1/OBF.1 requires de novo protein synthesis [23].
  • Here, we identified three additional previously uncharacterized distal enhancer modules of Nkx2-5: UH6, which directed transgene expression in the right ventricle, interventricular septum, and atrial ventricular canal; UH5, which directed expression in both atria; and UH4, which directed transgene expression in tongue muscle [27].

Analytical, diagnostic and therapeutic context of Myl4

  • We have used transgenesis to replace the ventricular isoform of the essential myosin light chain with the atrial isoform [28].
  • In situ hybridization, with 35S-labeled antisense cRNAs, demonstrates the versatility of primary myotubes in that transcripts for (1) alpha-cardiac and alpha-skeletal actin, (2) MHCembryonic, MHCperinatal and MHC beta/slow, and (3) MLC1A, MLC1F and MLC3F are detectable at 14 days gestation [25].
  • Northern blot analysis revealed that the expression of mouse sarcolipin mRNA was most abundant in the atria and was undetectable in the ventricles, indicating an atrial chamber-specific expression pattern [29].
  • Northern blot, reverse transcriptase-linked polymerase chain reaction, RNase protection, and Western blot analysis revealed atrial restricted expression in the adult mouse heart, very low levels in aorta, and no detectable expression in ventricle, skeletal muscle, uterus, or liver [30].
  • A six-lead ECG was recorded from surface limb leads, and an octapolar electrode catheter was inserted via jugular vein cutdown approach for simultaneous atrial and ventricular endocardial recording and pacing [3].


  1. A skeletal muscle-specific enhancer regulated by factors binding to E and CArG boxes is present in the promoter of the mouse myosin light-chain 1A gene. Catala, F., Wanner, R., Barton, P., Cohen, A., Wright, W., Buckingham, M. Mol. Cell. Biol. (1995) [Pubmed]
  2. Evaluation of the role of I(KACh) in atrial fibrillation using a mouse knockout model. Kovoor, P., Wickman, K., Maguire, C.T., Pu, W., Gehrmann, J., Berul, C.I., Clapham, D.E. J. Am. Coll. Cardiol. (2001) [Pubmed]
  3. Induction of atrial tachycardia and fibrillation in the mouse heart. Wakimoto, H., Maguire, C.T., Kovoor, P., Hammer, P.E., Gehrmann, J., Triedman, J.K., Berul, C.I. Cardiovasc. Res. (2001) [Pubmed]
  4. Gene dose-dependent atrial arrhythmias, heart block, and brady-cardiomyopathy in mice overexpressing A(3) adenosine receptors. Fabritz, L., Kirchhof, P., Fortmüller, L., Auchampach, J.A., Baba, H.A., Breithardt, G., Neumann, J., Boknik, P., Schmitz, W. Cardiovasc. Res. (2004) [Pubmed]
  5. Nkx2-5 pathways and congenital heart disease; loss of ventricular myocyte lineage specification leads to progressive cardiomyopathy and complete heart block. Pashmforoush, M., Lu, J.T., Chen, H., Amand, T.S., Kondo, R., Pradervand, S., Evans, S.M., Clark, B., Feramisco, J.R., Giles, W., Ho, S.Y., Benson, D.W., Silberbach, M., Shou, W., Chien, K.R. Cell (2004) [Pubmed]
  6. Cardiac malformations, adrenal agenesis, neural crest defects and exencephaly in mice lacking Cited2, a new Tfap2 co-activator. Bamforth, S.D., Bragança, J., Eloranta, J.J., Murdoch, J.N., Marques, F.I., Kranc, K.R., Farza, H., Henderson, D.J., Hurst, H.C., Bhattacharya, S. Nat. Genet. (2001) [Pubmed]
  7. Membrane guanylate cyclase is a cell-surface receptor with homology to protein kinases. Singh, S., Lowe, D.G., Thorpe, D.S., Rodriguez, H., Kuang, W.J., Dangott, L.J., Chinkers, M., Goeddel, D.V., Garbers, D.L. Nature (1988) [Pubmed]
  8. Atypical beta-adrenoceptor on brown adipocytes as target for anti-obesity drugs. Arch, J.R., Ainsworth, A.T., Cawthorne, M.A., Piercy, V., Sennitt, M.V., Thody, V.E., Wilson, C., Wilson, S. Nature (1984) [Pubmed]
  9. Enhanced myocardial function in transgenic mice overexpressing the beta 2-adrenergic receptor. Milano, C.A., Allen, L.F., Rockman, H.A., Dolber, P.C., McMinn, T.R., Chien, K.R., Johnson, T.D., Bond, R.A., Lefkowitz, R.J. Science (1994) [Pubmed]
  10. In vivo cardiac electrophysiology studies in the mouse. Berul, C.I., Aronovitz, M.J., Wang, P.J., Mendelsohn, M.E. Circulation (1996) [Pubmed]
  11. Antiarrhythmic activity of p-hydroxy-N-(2-diethylaminoethyl) benzamide (the p-hydroxy isostere of procainamide) in dogs and mice. Drayer, D.E., Slaven, B.H., Reidenberg, M.M., Bagwell, E.E., Cordova, M. J. Med. Chem. (1977) [Pubmed]
  12. Effects of total replacement of atrial myosin light chain-2 with the ventricular isoform in atrial myocytes of transgenic mice. Pawloski-Dahm, C.M., Song, G., Kirkpatrick, D.L., Palermo, J., Gulick, J., Dorn, G.W., Robbins, J., Walsh, R.A. Circulation (1998) [Pubmed]
  13. The cardiac tissue-restricted homeobox protein Csx/Nkx2.5 physically associates with the zinc finger protein GATA4 and cooperatively activates atrial natriuretic factor gene expression. Lee, Y., Shioi, T., Kasahara, H., Jobe, S.M., Wiese, R.J., Markham, B.E., Izumo, S. Mol. Cell. Biol. (1998) [Pubmed]
  14. Control of segmental expression of the cardiac-restricted ankyrin repeat protein gene by distinct regulatory pathways in murine cardiogenesis. Kuo, H., Chen, J., Ruiz-Lozano, P., Zou, Y., Nemer, M., Chien, K.R. Development (1999) [Pubmed]
  15. Downregulation of atrial markers during cardiac chamber morphogenesis is irreversible in murine embryos. Gruber, P.J., Kubalak, S.W., Chien, K.R. Development (1998) [Pubmed]
  16. Cardiomyocytes can be generated from marrow stromal cells in vitro. Makino, S., Fukuda, K., Miyoshi, S., Konishi, F., Kodama, H., Pan, J., Sano, M., Takahashi, T., Hori, S., Abe, H., Hata, J., Umezawa, A., Ogawa, S. J. Clin. Invest. (1999) [Pubmed]
  17. Developmental regulation of myosin gene expression in mouse cardiac muscle. Lyons, G.E., Schiaffino, S., Sassoon, D., Barton, P., Buckingham, M. J. Cell Biol. (1990) [Pubmed]
  18. Myosin light chain gene expression in developing and denervated fetal muscle in the mouse. Barton, P.J., Harris, A.J., Buckingham, M.E. Development (1989) [Pubmed]
  19. Structure and sequence of the myosin alkali light chain gene expressed in adult cardiac atria and fetal striated muscle. Barton, P.J., Robert, B., Cohen, A., Garner, I., Sassoon, D., Weydert, A., Buckingham, M.E. J. Biol. Chem. (1988) [Pubmed]
  20. Fetal cardiac natriuretic peptide expression and cardiovascular hemodynamics in endotoxin-induced acute cardiac dysfunction in mouse. Mäkikallio, K., Rounioja, S., Vuolteenaho, O., Paakkari, J., Hallman, M., Räsänen, J. Pediatr. Res. (2006) [Pubmed]
  21. Gene expression of phenylethanolamine N-methyltransferase in corticotropin-releasing hormone knockout mice during stress exposure. Kvetnansky, R., Kubovcakova, L., Tillinger, A., Micutkova, L., Krizanova, O., Sabban, E.L. Cell. Mol. Neurobiol. (2006) [Pubmed]
  22. Atrial-like phenotype is associated with embryonic ventricular failure in retinoid X receptor alpha -/- mice. Dyson, E., Sucov, H.M., Kubalak, S.W., Schmid-Schönbein, G.W., DeLano, F.A., Evans, R.M., Ross, J., Chien, K.R. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  23. Myosin light chain 1 atrial isoform (MLC1A) is expressed in pre-B cells under control of the BOB.1/OBF.1 coactivator. Laumen, H., Brunner, C., Greiner, A., Wirth, T. Nucleic Acids Res. (2004) [Pubmed]
  24. The expression of myosin genes in developing skeletal muscle in the mouse embryo. Lyons, G.E., Ontell, M., Cox, R., Sassoon, D., Buckingham, M. J. Cell Biol. (1990) [Pubmed]
  25. Contractile protein gene expression in primary myotubes of embryonic mouse hindlimb muscles. Ontell, M., Ontell, M.P., Sopper, M.M., Mallonga, R., Lyons, G., Buckingham, M. Development (1993) [Pubmed]
  26. Promoter analysis of myosin alkali light chain genes expressed in mouse striated muscle. Cohen, A., Barton, P.J., Robert, B., Garner, I., Alonso, S., Buckingham, M.E. Nucleic Acids Res. (1988) [Pubmed]
  27. Complex cardiac Nkx2-5 gene expression activated by noggin-sensitive enhancers followed by chamber-specific modules. Chi, X., Chatterjee, P.K., Wilson, W., Zhang, S.X., Demayo, F.J., Schwartz, R.J. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  28. Functional significance of cardiac myosin essential light chain isoform switching in transgenic mice. Fewell, J.G., Hewett, T.E., Sanbe, A., Klevitsky, R., Hayes, E., Warshaw, D., Maughan, D., Robbins, J. J. Clin. Invest. (1998) [Pubmed]
  29. Atrial chamber-specific expression of sarcolipin is regulated during development and hypertrophic remodeling. Minamisawa, S., Wang, Y., Chen, J., Ishikawa, Y., Chien, K.R., Matsuoka, R. J. Biol. Chem. (2003) [Pubmed]
  30. Chamber specification of atrial myosin light chain-2 expression precedes septation during murine cardiogenesis. Kubalak, S.W., Miller-Hance, W.C., O'Brien, T.X., Dyson, E., Chien, K.R. J. Biol. Chem. (1994) [Pubmed]
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