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|Coordinate||80,246,451 bp (GRCm38)|
|Base Change||T ⇒ A (forward strand)|
|Gene Name||myosin VI|
|Chromosomal Location||80,165,031-80,311,729 bp (+)|
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] This gene encodes a reverse-direction motor protein that moves toward the minus end of actin filaments and plays a role in intracellular vesicle and organelle transport. The protein consists of a motor domain containing an ATP- and an actin-binding site and a globular tail which interacts with other proteins. This protein maintains the structural integrity of inner ear hair cells and mutations in this gene cause non-syndromic autosomal dominant and recessive hearing loss. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2014]
PHENOTYPE: Homozygous mutant mice exhibit deafness and related behavioral characteristics such as circling, head tossing and hyperactivity. Progressive degeneration of the cochlear hair cells and the organ of Corti is observed with one mutation. [provided by MGI curators]
|Amino Acid Change||Cysteine changed to Stop codon|
|Institutional Source||Beutler Lab|
C236* in Ensembl: ENSMUSP00000036181 (fasta)
|Gene Model||not available|
|Alleles Listed at MGI|
|Mode of Inheritance||Autosomal Recessive|
|Local Stock||Sperm, gDNA|
|Last Updated||2018-05-22 9:35 AM by Anne Murray|
|Record Created||2009-09-30 12:00 AM|
The mayday circler phenotype was identified in a group of ENU-mutagenized mice to be tested for suppression of the mayday phenotype. Mayday circler mice exhibit bidirectional circling and head tilting ('stargazing'), phenotypes that are much more apparent when the mice are alone.
|Nature of Mutation|
The mayday circler mutation was mapped by bulk segregation analysis (BSA) of F2 backcross offspring using C57BL/10J as the mapping strain (n=13 mice mutant phenotype, 13 with normal phenotype) . The mutation showed strongest linkage with marker B10SNPS0144 at position 87513872 bp on Chromosome 9 (synthetic LOD=7.8, P=2.48x10-4). Myo6, located 7.5 Mb from B10SNPS0144, was identified as a candidate gene that when mutated causes circling, head tossing, and hyperactive behavior, and was directly sequenced. A T to A transversion at position 929 of the Myo6 transcript, in exon 9 of 33 total exons, was found in mayday circler mice.
912 GAGAAGTCTAGGATCTGTGTTCAAGGCAAAGAG 231 -E--K--S--R--I--C--V--Q--G--K--E-
The mutated nucleotide (red) converts codon 236, normally encoding cysteine, to a premature stop codon.
Myosins are actin-based molecular motors for various cellular cargoes, producing mechanical force through repeated cycles of ATP hydrolysis. They are composed of one or two heavy chains and one to six non-covalently associated light chains. All myosins contain a catalytic head or motor domain containing ATP- and actin-binding sites. Within the motor domain is a converter domain that undergoes an ~70° rotation powered by ATP hydrolysis in the myosin head. Connected to the converter are one or more calmodulin light chain-binding domains (also called IQ domains) that form an extension from the myosin catalytic domain known as the lever arm or neck. This lever arm amplifies the movements of the converter domain, which transitions between pre-stroke and post-stroke states, providing the power for movement along an actin filament. Myosins are classified into some 30 classes based on differences in the sequences of their motor domains (1); each class also has a characteristic and distinct tail domain (2). Myosins are also divided into conventional (muscle myosins and myosins similar in structure and function to muscle myosins, all belonging to class II) and unconventional classes (myosins that do not resemble muscle myosins). Myosin VI is a 1262-amino acid unconventional myosin heavy chain (MHC).
Myosin VI dimers can move processively with a relatively large 30-36 nm step size along actin filaments (12;13), compared to ~10 nm for myosin II (14). This is in part due to the large arc of rotation through which myosin VI swings its lever arm with each power stroke (15;16). A rearrangement of the helices of the converter during the transition from pre-stroke to post-stroke states permits myosin VI to swing its lever arm through an arc of ~180° (17), much larger than the ~70° stroke characteristic of other myosins. However, even with the large lever arm rotation, the stroke size of a single myosin VI molecule truncated after the calmodulin-binding domain is only 12 nm (18), whereas that of a myosin VI dimer is 36 nm, suggesting that a lever arm extension is necessary to account for the full step size of myosin VI.
Long lever arms, typically resulting from the presence of many calmodulin-binding sites, result in a large step size, as for example in myosin V that has six calmodulin-binding sites and a step size of approximately 36 nm. However, the myosin VI lever arm contains only the insert-2 calmodulin-binding site and a second conventional calmodulin-binding site. Debate currently exists as to whether it is the proximal tail or medial tail that provides the lever arm extension that accounts for the large myosin VI step size. In support of the hypothesis that the medial tail domain acts to extend the lever arm of myosin VI, several reports provided evidence that the medial tail forms a rare, extended 10-nm single α-helix (rather than a coiled-coil as originally predicted (9)) that is sufficiently rigid to function as a mechanical extension (19;20). On the other hand, another group demonstrated that the proximal tail folds into a three-helix bundle that unfolds when myosin VI dimerizes (21). Dimerization could occur in a region located between the proximal and medial tails, and deletion of most of the medial tail did not impact the average step size or step size distribution, strongly suggesting that it is not the medial tail, but the flexible proximal tail that serves as the lever arm extension. Further studies are necessary to establish the structural basis of the large step size of myosin VI.
Myosin VI moves along actin toward the minus (pointed) end, in the opposite direction to all other myosins that have been characterized, which move towards the plus (barbed) end (22). This ability is imparted by structural adaptations that reposition the myosin VI lever arm to point in the opposite direction to that of other myosins. The unique insert is sufficient for lever arm repositioning in myosin VI (23;24). It interacts with the converter and thereby redirects the lever arm in the opposite direction (8).
The mayday circler mutation is located in the catalytic head domain, approximately 100 amino acids C-terminal to the ATP binding site (Figure 3).
By immunoblotting, myosin VI has been detected in all tissues examined: kidney cortex, intestinal mucosa, liver, lung, heart, jowl muscle, and brain (cortex and medulla) (9). It is most highly expressed in the kidney, where it is localized at the base of microvilli of proximal tubule cells (28). Myosin VI is localized at the apical brush border of intestinal enterocytes (29;30) and at the apical membrane of polarized human airway epithelial cells (Calu-3) (31). In the brain, myosin VI is localized to synapses and enriched at the postsynaptic density (32). In fibroblasts, myosin VI is found on the Golgi and at the leading edge after growth factor stimulation (33).
Myosin VI is expressed in the inner and outer hair cells of the sensory epithelium in the adult mouse cochlea (34;35). It was found concentrated within the actin-dense cuticular plate at the base of the stereocilia and in the pericuticular necklace around the cuticular plate, and it is present within stereocilia themselves (36). Myosin VI is detectable in presumptive hair cells by day 13.5 of gestation (37).
Myosin VI was first discovered in Drosophila melanogaster as a 140-kD actin-binding protein that is released from actin in the presence of ATP (38;39). Drosophila myosin VI, designated 95F myosin heavy chain, is encoded by at least three alternatively spliced transcripts and is expressed throughout fly development. 95F is required for the transport of cytoplasmic particles (40) during organization of the embryonic syncytial blastoderm (41), and during oogenesis (42). It also functions in asymmetric protein localization in Drosophila neuroblasts (43), and in stabilization of the armadillo (Drosophila β-catenin)-cadherin complex in the ovary (44), which are required for proper mitotic spindle orientation and cell migration, respectively. In addition, 95F is essential for spermatogenesis, and mutations in 95F result in male sterility due to a failure in spermatid individualization (45). In 95F mutants, stabilization of the branched actin network between distinct spermatids (46), and localization of the actin polymerization regulatory proteins cortactin and the Arp2/3 complex are impaired (47).
Mutations in MYO6 are associated with hearing loss in humans. In contrast to the recessive inheritance pattern of Myo6 phenotypes in mice, in humans MYO6 mutations have been linked with both dominant (OMIM #606346) (52) and recessive non-syndromic hearing loss (OMIM #607821) (53), as well as with dominant syndromic hearing loss that includes hypertrophic cardiomyopathy (54). A dominantly inherited atrial septal defect has also been shown to be caused by a missense mutation in myosin VI (55). Overexpression of myosin VI has been observed in human prostate cancer specimens (56), and contributes to enhanced prostate-specific antigen (PSA) and vascular endothelial growth factor (VEGF) secretion by a prostate cancer cell line (LNCaP) (57).
Myosin VI is involved in membrane trafficking, both exocytosis and endocytosis [reviewed in (58)]. Myosin VI is present in vesicles at the Golgi complex, and fibroblasts derived from Myo6sv/sv mice display a 40% reduction in the size of the Golgi network as well as a 40% reduction in protein secretion from the trans Golgi network to the plasma membrane (33;59). These defects are rescued by expression of full length myosin VI. In polarized MDCK cells, the myosin VI isoform lacking the tail domain insert is required for sorting and transport to the basolateral membrane of newly synthesized proteins containing a tyrosine-based sorting motif via the AP-1B complex (60). Myosin VI is recruited to the Golgi complex by optineurin (61) and the small G-protein Rab8; these proteins may form a transport complex for proteins destined for the basolateral membrane in polarized epithelial cells (Figure 4C)(60). However, since actin is generally oriented with minus ends pointing into the cell, it remains unclear how a minus end-directed motor would mediate this type of transport.
Minus end-directed transport by myosin VI is consistent with a role in endocytosis, and strong evidence supports a role for myosin VI in this process (Figure 4A). Myo6sv/sv fibroblasts exhibit abnormally shallow clathrin-coated pits and reduced internalization of clathrin-coated vesicles (62). Myosin VI can be detected at the base of the brush border in kidney proximal tubule cells, closely associated with AP-2 at the intermicrovillar coated pit region (28), where it is required for endocytosis-mediated protein absorption by the kidney (63). Similarly, myosin VI is localized at the apical brush border of intestinal enterocytes (29;30) and at the apical membrane of polarized human airway epithelial cells (Calu-3) (31), where it is necessary for endocytosis of cystic fibrosis transmembrane conductance regulator (CFTR). Finally, myosin VI exists in a complex with AP-2, SAP97, and AMPA receptors in the brain, and is required for stimulation-induced internalization of AMPA receptors in hippocampal neurons likely by clathrin-mediated endocytosis (32;64). Myosin VI deficiency results in reductions in synapse number, changes in synapse structure, and astrogliosis (32;65).
The function of myosin VI in endocytosis may depend on the cell type in which it is functioning and/or on the isoform of myosin VI present. One report suggested that the myosin VI isoform containing the large insert is preferentially expressed in polarized epithelial cells with microvilli, while the isoform containing the small or no insert is predominantly expressed in cells lacking microvilli (11). Large-insert myosin VI colocalized with clathrin-coated pits via its cargo-binding domain in a polarized colorectal adenocarcinoma cell line (Caco-2) and in nonpolarized rat kidney cells, and could be immunoprecipitated in a complex containing AP-2 and clathrin (11). Overexpression of the tail domain containing the large insert reduced endocytosis by 50%, as measured by transferrin receptor uptake, whereas overexpression of the tail domain lacking the insert had no effect on endocytosis. The presence of the large tail domain insert also enhanced myosin VI localization to clathrin-coated pits. These findings suggested that myosin VI containing the large insert may function at an early stage of endocytosis, such as during invagination, pinching off, or early transport prior to uncoating.
In contrast, in a retinal pigmented epithelial cell line (ARPE-19), myosin VI lacking the tail domain insert was not present on clathrin-coated pits but instead was transiently recruited to transferrin-containing newly uncoated endocytic vesicles before fusion with early endosomes (66). Overexpression of the myosin VI tail domain with no insert reduced the rate of transferrin receptor uptake. Rescue of the defect in clathrin-mediated endocytosis in Myo6sv/sv fibroblasts by re-expression of the no-insert isoform demonstrated that this isoform can perform all myosin VI functions necessary for endocytosis (62). Further work suggested that myosin VI moves endocytic vesicles through the actin-rich region at the cell periphery for fusion with the early endosome (67). Thus, myosin VI is essential for normal endocytosis, but it remains unclear whether large-insert and no-insert isoforms of myosin VI possess distinct functions, or whether its role in endocytosis is cell type-specific.
Multiple regulatory mechanisms modulate the activity of myosin VI: 1) The expression of alternatively spliced isoforms that may carry out distinct cellular functions, as described above. 2) Myosin VI is phosphorylated at multiple sites (33), which may regulate the binding of interactors such as optineurin (61). 3) Calcium binding to the calmodulin light chain may affect the kinetic properties of myosin VI. Increases in calcium concentration have been shown to reduce the rate of ADP release and movement along actin filaments in an artificial myosin VI dimer (68). 4) Myosin VI binds strongly to the phosphoinositide PI(4,5)P2, an interaction that promotes dimerization and localization to clathrin-coated pits (72). 5) The binding of adapters and interactors has been shown to result in myosin VI dimerization from the folded monomeric state, thus activating processive motor activity along actin filaments. It has been postulated that monomeric myosin VI can more effectively diffuse through actin networks to the cell periphery where it appears to act.
Binding partners enable myosin VI to carry out its specific cellular functions. As mentioned above, optineurin and Rab8 link myosin VI to the Golgi complex (61) to facilitate exocytosis and to maintain Golgi structure. Disabled-2 (Dab2) is another myosin VI binding partner present on endocytic clathrin-coated structures at the plasma membrane (69). Dab2 plays a key role in clathrin-mediated endocytosis of members of the low density lipoprotein receptor (LDLR) family by interacting with PIP2, AP-2, and clathrin (70;71). Myosin VI is recruited to clathrin coated pits by binding to Dab2 and PIP2 (72). A complex containing Dab2, AP-2, and myosin VI mediates endocytosis of CFTR channels in the intestine (73). GIPC and SAP97 are also myosin VI adapters that may mediate endocytosis of transmembrane receptors such as the LDL receptor megalin, human lutropin receptor, and the β-1 adrenergic receptor (74), and AMPA receptors (32), respectively. GIPC also couples myosin VI to uncoated endocytic vesicles (74). TRAF6-binding protein (T6BP) was identified as a myosin VI binding protein by yeast two-hybrid assay; since T6BP was found to inhibit NF-κB activation, myosin VI-T6BP interactions may link membrane trafficking and cytoskeletal organization with cytokine-dependent signaling (75). Myosin VI and vinculin were recently shown to interact during the formation of cadherin-based adhesive contacts between cultured epithelial cells (76). Finally, although previously presumed to localized solely to the cytoplasm, myosin VI has been identified in the nucleus of mammalian cells, where it modulates the RNA polymerase II-dependent transcription of active genes (77).
The phenotype of mayday circler mice is consistent with a functionally null mutation. The mayday circler mutation converts codon 236, normally encoding cysteine, to a premature stop codon that may trigger nonsense mediated decay of the transcript, resulting in complete absence of the protein in the mouse. It has been hypothesized that the hair cells of the cochlea are particularly sensitive to myosin VI deficiency because they lack compensatory mechanisms for coping with loss of myosin VI function. Thus, Myo6 mutants display inner ear defects, but otherwise develop and reproduce relatively normally. In support of this hypothesis, it has been observed in fibroblasts that caveolae-dependent endocytosis can partially compensate for impaired clathrin-mediated endocytosis resulting from deficiency of myosin VI (62).
|Primers||Primers cannot be located by automatic search.|
Mayday circler genotyping is performed by amplifying the region containing the mutation using PCR, followed by sequencing of the amplified region to detect the single nucleotide change.
mayday circler (F): 5’-ACAGCAGATTTTCATGGTGGTGAGC -3’
mayday circler (R): 5’- CCTGAGATCCTGGTGTGACAAAGC -3’
1) 95°C 2:00
2) 95°C 0:30
3) 56°C 0:30
4) 72°C 1:00
5) repeat steps (2-4) 29X
6) 72°C 7:00
7) 4°C ∞
Primers for sequencing
mayday circler_seq(F): 5’- TGCACTGCTAAGTCAGTTCTG -3’
mayday circler_seq(R): 5’- AGTTTGCACCCAAGGTCTG -3’
The following sequence of 916 nucleotides (from Genbank genomic region NC_000075 for linear genomic sequence of Myo6, sense strand) is amplified:
81061 attttcatgg tggtgagctg agagctcttt agcaacagtc tatgggctgc tgtggacact
81121 ggtgtgcact gctaagtcag ttctgattct ggagaggctc agggtagaga ttggataaca
81181 atgtttaaaa tgaaggagaa ataatcaaag cttacattgt aggtgtcttt gtctagtatt
81241 taataaacat tttaacttct ttgacaagca aatgtttatt agaaaaagtt agtttagcat
81301 tgagttatat ttcaatccca cggatataaa atgtattttc tattttgtct tttagagttc
81361 ggttgttgga ggatttgttt cccattacct tctagagaag tctaggatct gtgttcaagg
81421 caaagaggag cggaattacc atattttcta caggctctgt gctggggctt cagaagacat
81481 cagggagaag cttcacttga gctccccaga taatttccgg gtaggttgga ggaaaataaa
81541 ttttatacca ggtttgcaaa tcgttcttcg tcctaaaact tactggtttt ggagtcctac
81601 ttgtttttgt acataactta tgttaaatca agcacagtgg gctttctggg cttgcagagt
81661 ttcatctcaa gattaactat gaattgcaaa taatgggaat gataaagaga gcacctctgg
81721 aggaggacac aacatctgcc ccaacaccag aattaactgg gaccagcggg acctaggaac
81781 tctgtctgac ccgtggcatg ggttccttcc cgtctgagcc agtgccctga gcagaccttg
81841 ggtgcaaact ccacagccag tcccacaaca cccagaggaa gctcttctcc caggcactct
81901 aacactccca ggtccacagg atcccaggat cccaggatcc caagagcttt gtcacaccag
Primer binding sites are underlined; sequencing primer binding sites are highlighted in gray; the mutated T is indicated in red.
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38. Kellerman, K. A., and Miller, K. G. (1992) An Unconventional Myosin Heavy Chain Gene from Drosophila Melanogaster. J. Cell Biol. 119, 823-834.
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57. Puri, C., Chibalina, M. V., Arden, S. D., Kruppa, A. J., Kendrick-Jones, J., and Buss, F. (2010) Overexpression of Myosin VI in Prostate Cancer Cells Enhances PSA and VEGF Secretion, but has no Effect on Endocytosis. Oncogene. 29, 188-200.
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61. Sahlender, D. A., Roberts, R. C., Arden, S. D., Spudich, G., Taylor, M. J., Luzio, J. P., Kendrick-Jones, J., and Buss, F. (2005) Optineurin Links Myosin VI to the Golgi Complex and is Involved in Golgi Organization and Exocytosis. J. Cell Biol. 169, 285-295.
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66. Aschenbrenner, L., Lee, T., and Hasson, T. (2003) Myo6 Facilitates the Translocation of Endocytic Vesicles from Cell Peripheries. Mol. Biol. Cell. 14, 2728-2743.
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70. Mishra, S. K., Keyel, P. A., Hawryluk, M. J., Agostinelli, N. R., Watkins, S. C., and Traub, L. M. (2002) Disabled-2 Exhibits the Properties of a Cargo-Selective Endocytic Clathrin Adaptor. EMBO J. 21, 4915-4926.
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73. Collaco, A., Jakab, R., Hegan, P., Mooseker, M., and Ameen, N. (2010) Alpha-AP-2 Directs Myosin VI-Dependent Endocytosis of Cystic Fibrosis Transmembrane Conductance Regulator Chloride Channels in the Intestine. J. Biol. Chem. 285, 17177-17187.
74. Naccache, S. N., Hasson, T., and Horowitz, A. (2006) Binding of Internalized Receptors to the PDZ Domain of GIPC/synectin Recruits Myosin VI to Endocytic Vesicles. Proc. Natl. Acad. Sci. U. S. A. 103, 12735-12740.
75. Morriswood, B., Ryzhakov, G., Puri, C., Arden, S. D., Roberts, R., Dendrou, C., Kendrick-Jones, J., and Buss, F. (2007) T6BP and NDP52 are Myosin VI Binding Partners with Potential Roles in Cytokine Signalling and Cell Adhesion. J. Cell. Sci. 120, 2574-2585.
76. Maddugoda, M. P., Crampton, M. S., Shewan, A. M., and Yap, A. S. (2007) Myosin VI and Vinculin Cooperate during the Morphogenesis of Cadherin Cell Cell Contacts in Mammalian Epithelial Cells. J. Cell Biol. 178, 529-540.
|Science Writers||Eva Marie Y. Moresco|
|Illustrators||Diantha La Vine|
|Authors||Sungyong Won, Bruce Beutler|
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