Myosin-7b Promotes Distal Tip Localization of the Intermicrovillar Adhesion Complex.
Transporting epithelial cells interact with the luminal environment using a tightly packed array of microvilli known as the brush border. During intestinal epithelial differentiation, microvillar packing and organization are driven by cadherin-dependent adhesion complexes that localize to the distal tips of microvilli, where they drive physical interactions between neighboring protrusions. Although enrichment of the "intermicrovillar adhesion complex" (IMAC) at distal tips is required for proper function, the mechanism driving tip accumulation of these factors remains unclear. Here, we report that the actin-based motor myosin-7b (Myo7b) promotes the accumulation of IMAC components at microvillar tips. Myo7b is highly enriched at the tips of microvilli in both kidney and intestinal brush borders, and loss of Myo7b in differentiating intestinal epithelial cells disrupts intermicrovillar adhesion and, thus, brush border assembly. Analysis of cells lacking Myo7b revealed that IMAC components and the resulting intermicrovillar adhesion links are mislocalized along the microvillar axis rather than enriched at the distal tips. We also found that Myo7b motor domains are capable of supporting tip-directed transport. However, motor activity is supplemented by other passive targeting mechanisms that together drive highly efficient IMAC accumulation at the tips. These findings illuminate the molecular basis of IMAC enrichment at microvillar tips and hold important implications for understanding apical morphogenesis in transporting and sensory epithelial tissues.
Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37240, USA.
Meredith L
ML
Weck
Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37240, USA.
Scott W
SW
Crawley
Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37240, USA.
Colin R
CR
Stone
Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37240, USA. Electronic address: matthew.tyska@vanderbilt.edu.
Matthew J
MJ
Tyska
D000818:Animals; D018938:Caco-2 Cells; D004847:Epithelial Cells / Q000378:metabolism*; D006801:Humans; D018374:LLC-PK1 Cells; D008871:Microvilli / Q000378:metabolism*; D018995:Myosin Heavy Chains / Q000235:genetics* / Q000378:metabolism; D013552:Swine
D018995:Myosin Heavy Chains
Myo7b; actin; brush border; cytoskeleton; epithelia; intermicrovillar adhesion; motor protein; protrusion
Development. 1998 Feb;125(4):557-66
9435277
Physiology (Bethesda). 2012 Feb;27(1):25-42
22311968
Proc Natl Acad Sci U S A. 2009 Mar 17;106(11):4189-94
19255446
Curr Biol. 2001 Mar 6;11(5):318-29
11267868
Proc Natl Acad Sci U S A. 2009 Oct 13;106(41):17320-4
19805065
Nat Cell Biol. 2005 Feb;7(2):148-56
15654330
Cell. 2014 Apr 10;157(2):433-46
24725409
Mol Biol Cell. 2010 Mar 15;21(6):970-8
20089841
Curr Biol. 2009 Jun 9;19(11):967-73
19398338
Can J Gastroenterol. 2001 Jan;15(1):61-4
11173328
Mol Cell Biol. 2010 Apr;30(7):1703-17
20123970
Curr Biol. 2011 Jan 25;21(2):167-72
21236676
Mol Biol Cell. 2004 May;15(5):2253-63
15004223
J Cell Sci. 1994 Dec;107 ( Pt 12):3535-43
7706404
Science. 1991 Oct 25;254(5031):539-44
1948029
J Cell Biol. 1975 Dec;67(3):725-43
1202021
Development. 2008 Apr;135(8):1427-37
18339676
Genomics. 2001 Mar 15;72(3):285-96
11401444
J Biol Chem. 2005 Nov 25;280(47):39665-76
16186105
Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):13958-63
14610277
Nat Genet. 2000 Sep;26(1):56-60
10973248
Cell. 2009 Aug 7;138(3):537-48
19665975
J Biol Chem. 1998 Aug 7;273(32):20334-40
9685384
Proc Natl Acad Sci U S A. 2006 Aug 15;103(33):12411-6
16894163
J Cell Sci. 2014 Aug 15;127(Pt 16):3535-45
24928903
J Biol Chem. 1999 Jun 4;274(23):16400-6
10347200
Nat Cell Biol. 2002 Mar;4(3):246-50
11854753
Curr Biol. 2012 Feb 21;22(4):320-5
22264607
Proc Natl Acad Sci U S A. 2006 Apr 11;103(15):5746-51
16585515
Proc Natl Acad Sci U S A. 1994 Jul 5;91(14):6549-53
8022818
Nat Genet. 1997 Jun;16(2):191-3
9171833
Nat Cell Biol. 2004 Jun;6(6):523-31
15156152
Can J Gastroenterol. 2002 Nov;16(11):771-8
12464970
J Biol Chem. 2015 Jul 10;290(28):17587-98
26001786
Mol Cell. 2006 Feb 3;21(3):331-6
16455488
Biochemistry. 1997 Nov 18;36(46):14037-43
9369475
J Biol Chem. 2005 Sep 16;280(37):32061-8
16055438
Ultrastruct Pathol. 2011 Apr;35(2):87-91
21299349
Biochem Biophys Res Commun. 2004 Jun 18;319(1):214-20
15158464
Proc Natl Acad Sci U S A. 2011 Apr 26;108(17 ):7028-33
21482763
J Am Soc Nephrol. 2005 Oct;16(10):2890-6
16107581
Biochemistry. 2003 Jan 14;42(1):90-5
12515542
Nature. 2005 Aug 25;436(7054):1113-8
16121172
Dev Cell. 2016 Jan 25;36(2):190-200
26812018
Curr Biol. 2012 Apr 10;22(7):627-31
22386311
Am J Hum Genet. 1996 Nov;59(5):1074-83
8900236
Proc Natl Acad Sci U S A. 2009 May 26;106(21):8483-8
19423668
Dev Cell. 2016 Jan 25;36(2):179-89
26812017
Proc Natl Acad Sci U S A. 2011 Jul 12;108(28):11476-81
21709241
Nat Cell Biol. 2009 Apr;11(4):443-50
19287378