Differential roles for 3-OSTs in the regulation of cilia length and motility.
As cells integrate molecular signals from their environment, cell surface receptors require modified proteoglycans for the robust activation of signaling pathways. Heparan sulfate proteoglycans (HSPGs) have long unbranched chains of repetitive disaccharide units that can be sulfated at specific positions by heparan sulfate O-sulfotransferase (OST) families. Here, we show that two members of the 3-OST family are required in distinct signaling pathways to control left-right (LR) patterning through control of Kupffer's vesicle (KV) cilia length and motility. 3-OST-5 functions in the fibroblast growth factor pathway to control cilia length via the ciliogenic transcription factors FoxJ1a and Rfx2. By contrast, a second 3-OST family member, 3-OST-6, does not regulate cilia length, but regulates cilia motility via kinesin motor molecule (Kif3b) expression and cilia arm dynein assembly. Thus, two 3-OST family members cell-autonomously control LR patterning through distinct pathways that regulate KV fluid flow. We propose that individual 3-OST isozymes create distinct modified domains or 'glycocodes' on cell surface proteoglycans, which in turn regulate the response to diverse cell signaling pathways.
Department of Neurobiology and Anatomy, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
Judith M
JM
Neugebauer
Adam B
AB
Cadwallader
Jeffrey D
JD
Amack
Brent W
BW
Bisgrove
H Joseph
HJ
Yost
D000825:Animal Structures / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D019521:Body Patterning / Q000187:drug effects; D002923:Cilia / Q000187:drug effects / Q000201:enzymology* / Q000648:ultrastructure; D004398:Dyneins / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000378:metabolism / Q000648:ultrastructure; D005346:Fibroblast Growth Factors / Q000378:metabolism; D016547:Kinesins / Q000378:metabolism; D008954:Models, Biological; D060172:Morpholinos / Q000494:pharmacology; D009068:Movement / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D015238:Sulfotransferases / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000378:metabolism*
D060172:Morpholinos; D014157:Transcription Factors; D029961:Zebrafish Proteins; D005346:Fibroblast Growth Factors; D015238:Sulfotransferases; D004398:Dyneins; D016547:Kinesins
3-OST; Cilia; FGF; Fibroblast growth factors; Fluid flow; Glycocode; Gut asymmetry; HSPG; Heart asymmetry; Heparan sulfate proteoglycans; Left-right development; O-Sulfotransferase; OST; Zebrafish