H. Joseph Yost, Ph.D., research
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Research authored by Dr. Yost and his lab
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Wings of HOPE as we REACH for the CURE to Multiple Hereditary Exostoses / Multiple Osteochondroma
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2009 Conference abstract
HS Fine Structure and FGF Signaling Pathways Converge at Cilia: Does Cilia Function Have a Role in HME?
H. Joseph Yost, Ph.D.
Departments of Neurobiology & Anatomy, Pediatrics. University of Utah School of Medicine.
http://yost.genetics.utah.edu
Several peptide growth factors, including members of the FGF, TGFb, BMP and Wnt families, have been implicated in the
regulation of cartilage and bone growth. The functions of these factors are regulated in part by complex Heparan Sulfate
Proteoglycans (HSPGs) at the cell surface. Alterations in genes involved in synthesis of Heparan Sulfate (HS) chains, as
exemplified by mutations in EXT1 and EXT2, lead to Hereditary Multiple Exostoses (HME), perhaps by misregulating complex cell-
cell signaling pathways. Heparan sulfate (HS) is an unbranched chain of repetitive disaccharides, typically attached to the core
proteins of Heparan sulfate proteoglycans (HSPGs), which specifically bind peptide growth factors at the cell surface or secreted
extracellularly. HS chains contain sulfated domains termed the HS "fine structure" which are catalyzed by HS O-sulfotransferases
(OSTs).
Our working hypothesis is that there is a "Glycocode" embedded in the fine structure of HS, and that distinct members of the
HS 3-OST family contribute to distinct signatures within this code, which then regulate specific cell-cell signaling pathways. Using
gene knock-down screens in zebrafish, we have uncovered distinct roles for three members, 3-OST-5, 3-OST-6 and 3-OST-3Z
expressed in the same cell lineages. Strikingly, both 3-OST-5 and 3-OST-6 are required for distinct functions of cilia, which are
cell surface organelles found on most epithelia in vertebrates. Recently, cilia have been implicated as recipients of some cell-cell
signaling pathways, for example, Hedgehog signaling. However, little is known about cell-cell signaling pathways that control the
formation or function of cilia. We found that 3-OST-5 is required for normal cilia length, whereas 3-OST-6 controls cilia motility.
Knockdown of a third 3-OST family member has normal cilia function. In collaboration with Jeff Esko’s lab, we find that
knockdowns of each of these three 3-OST family members cause a similar reduction of a 3-O-sulfated disaccharide subunit in
the HS chains, so the differences in cellular phenotypes are not simply due to bulk changes in sulfation. Further analyses indicate
that 3-OST-5 and 3-OST-6 modulate distinct cell-cell signaling pathways in cilia formation or function, presumably by distinct
glycocodes.
Using several genetic, morpholino and pharmacological approaches, we have recently shown that fibroblast growth factor (FGF)
signaling, via FGF8, FGF24 and FGF receptor1 (FGFR1), regulates cilia length and function in diverse epithelia during zebrafish
and Xenopus development (Neugebauer et al., 2009 Nature). Strikingly, both FGFR1- and 3-OST-5-dependent pathways
converge on the same Intraflagellar Transport (IFT) regulatory pathway to control cilia length. These results suggest a
fundamental and highly conserved role for FGF signaling and 3-OST-5 in the regulation of cilia length in multiple tissues.
Given that cell signaling pathways and 3-OST-dependent fine structures converge on cilia formation and function, we propose
that a subset of developmental disorders ascribed HSPG misregulation, such as Hereditary Multiple Exostoses, might be due in
part to altered cilia function.
Photo's taken during the Third International MHE Research Conference
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