title: Growth factor-dependent branching of the ureteric bud is modulated by selective 6-O sulfation of heparan sulfate.
abstract: Heparan sulfate proteoglycans (HSPGs) are found in the basement membrane and at the cell-surface where they modulate the binding and activity of a variety of growth factors and other molecules. Most of the functions of HSPGs are mediated by the variable sulfated glycosaminoglycan (GAG) chains attached to a core protein. Sulfation of the GAG chain is key as evidenced by the renal agenesis phenotype in mice deficient in the HS biosynthetic enzyme, heparan sulfate 2-O sulfotransferase (Hs2st; an enzyme which catalyzes the 2-O-sulfation of uronic acids in heparan sulfate). We have recently demonstrated that this phenotype is likely due to a defect in induction of the metanephric mesenchyme (MM), which along with the ureteric bud (UB), is responsible for the mutually inductive interactions in the developing kidney (Shah et al., 2010). Here, we sought to elucidate the role of variable HS sulfation in UB branching morphogenesis, particularly the role of 6-O sulfation. Endogenous HS was localized along the length of the UB suggesting a role in limiting growth factors and other molecules to specific regions of the UB. Treatment of cultures of whole embryonic kidney with variably desulfated heparin compounds indicated a requirement of 6O-sulfation in the growth and branching of the UB. In support of this notion, branching morphogenesis of the isolated UB was found to be more sensitive to the HS 6-O sulfation modification when compared to the 2-O sulfation modification. In addition, a variety of known UB branching morphogens (i.e., pleiotrophin, heregulin, FGF1 and GDNF) were found to have a higher affinity for 6-O sulfated heparin providing additional support for the notion that this HS modification is important for robust UB branching morphogenesis. Taken together with earlier studies, these findings suggest a general mechanism for spatio-temporal HS regulation of growth factor activity along the branching UB and in the developing MM and support the view that specific growth factor-HSPG interactions establish morphogen gradients and function as developmental switches during the stages of epithelial organogenesis (Shah et al., 2004).
authors: Department of Medicine (Division of Nephrology and Hypertension), University of California, San Diego, La Jolla, California 92093, USA.
authors: Mita M
authors: MM
authors: Shah
authors: Hiroyuki
authors: H
authors: Sakurai
authors: Thomas F
authors: TF
authors: Gallegos
authors: Derina E
authors: DE
authors: Sweeney
authors: Kevin T
authors: KT
authors: Bush
authors: Jeffrey D
authors: JD
authors: Esko
authors: Sanjay K
authors: SK
authors: Nigam
references: J Biol Chem. 2002 Jan 25;277(4):2444-53
references: 11714710
references: Development. 2004 Apr;131(7):1563-75
references: 14998928
references: Development. 2008 Jan;135(2):301-10
references: 18077586
references: Curr Opin Nephrol Hypertens. 1995 May;4(3):209-14
references: 7648213
references: Dev Biol. 2004 Dec 15;276(2):403-15
references: 15581874
references: Prog Mol Biol Transl Sci. 2010;93:79-111
references: 20807642
references: Development. 2006 Dec;133(24):4933-44
references: 17107998
references: Development. 2007 Dec;134(23):4177-86
references: 17959718
references: J Cell Biol. 2006 Sep 11;174(6):773-8
references: 16966419
references: J Biol Chem. 2008 Apr 18;283(16):10366-76
references: 18281280
references: J Biol Chem. 2001 May 18;276(20):17014-21
references: 11278892
references: Glycoconj J. 2002 May-Jun;19(4-5):347-54
references: 12975615
references: J Biol Chem. 2009 Mar 6;284(10):6311-21
references: 19114710
references: Dev Biol. 2006 Mar 15;291(2):325-39
references: 16442091
references: Development. 2001 Sep;128(17):3283-93
references: 11546745
references: Proc Natl Acad Sci U S A. 1999 Jun 22;96(13):7330-5
references: 10377414
references: Dev Biol. 2004 Aug 15;272(2):310-27
references: 15282150
references: Am J Physiol. 1997 Sep;273(3 Pt 2):F463-72
references: 9321921
references: Dev Biol. 2010 Mar 15;339(2):354-65
references: 20059993
references: Dev Biol. 2004 Feb 15;266(2):285-98
references: 14738877
references: J Biol Chem. 1994 Dec 23;269(51):32279-85
references: 7528211
references: Am J Physiol. 1997 Nov;273(5):F757-67
references: 9374839
references: J Biol Chem. 2011 Apr 22;286(16):14435-44
references: 21357686
references: J Biol Chem. 2008 Apr 4;283(14):9308-17
references: 18230614
references: J Cell Biol. 2006 Jul 31;174(3):323-7
references: 16880267
references: Development. 1999 Feb;126(3):547-54
references: 9876183
references: Kidney Int. 1998 Dec;54(6):1832-42
references: 9853247
references: Birth Defects Res C Embryo Today. 2010 Mar;90(1):32-44
references: 20301217
references: Dev Biol. 2008 Jan 1;313(1):408-19
references: 18054902
references: J Biol Chem. 2005 Dec 23;280(51):42181-7
references: 16183643
references: Dev Biol. 2004 Nov 1;275(1):44-67
references: 15464572
references: Differentiation. 2006 Dec;74(9-10):638-47
references: 17177859
references: Am J Hypertens. 1988 Oct;1(4 Pt 1):335-47
references: 3063284
references: J Am Soc Nephrol. 2009 Jul;20(7):1465-9
references: 19056872
references: J Biol Chem. 2001 Sep 21;276(38):35429-34
references: 11457822
references: Dev Biol. 2010 Sep 15;345(2):204-14
references: 20637191
references: J Cell Biol. 2003 Nov 10;163(3):637-48
references: 14610064
references: J Biol Chem. 2006 Sep 15;281(37):26884-92
references: 16807244
references: Dev Biol. 2001 Oct 15;238(2):289-302
references: 11784011
references: Genes Dev. 1998 Jun 15;12(12):1894-906
references: 9637690
references: Biochemistry. 1999 Feb 9;38(6):1765-71
references: 10026256
references: Development. 2004 Jan;131(1):73-82
references: 14645127
references: J Clin Invest. 2001 Jul;108(2):169-73
references: 11457867
references: Development. 2004 Apr;131(7):1449-62
references: 15023929
references: Proc Natl Acad Sci U S A. 2001 Oct 23;98(22):12509-14
references: 11606725
references: Growth Factors. 2003 Sep-Dec;21(3-4):109-19
references: 14708939
references: J Clin Invest. 2003 Apr;111(7):989-99
references: 12671048
references: Biochim Biophys Acta. 2002 Dec 19;1573(3):312-8
references: 12417413
references: Physiology (Bethesda). 2004 Dec;19:339-47
references: 15546851
references: J Biol Chem. 1947 Jan;167(1):189-98
references: 20281638
references: Dev Biol. 1993 Oct;159(2):535-48
references: 8405677
references: Am J Physiol Renal Physiol. 2009 Nov;297(5):F1330-41
references: 19726549
references: J Biol Chem. 1993 Nov 15;268(32):23906-14
references: 7693696
references: Mech Dev. 2001 Dec;109(2):123-35
references: 11731227
references: Am J Kidney Dis. 1993 May;21(5 Suppl 2):66-72
references: 8494022