Recent studies have focused attention on the role of mitogenic niches in regulating stem cell? self?renewal, and have emphasized the importance of proteoglycans in forming such microenvironments.? However, more than 50 years after the genetic code was deciphered, we do not know? whether sugar chains on proteoglycans encode biologically important information. The potential? complexity of such a ?glyco code? is enormous, but little is known about the features of the? proteoglycans involved in mitogenic regulation, or the signaling mechanisms required for stem cell? renewal.? To decipher whether there is a glyco code we will identify proteoglycans that specify stem cell? renewal in the mammalian brain. We will rely on a genetic approach to proteoglycan biology and on? newly developing innovations in mass spectrometry that allow large scale analysis of the sugar? composition of proteoglycans. We will generate mutated growth factors capable of binding to cognate? receptors, but unable to bind proteoglycans. We will ascertain whether individual proteoglycans? modulate the signaling pathway and the biological response elicited by a growth factor, perhaps by? influencing the location, presentation, or oligomerization of the factor. We will begin by focusing on? Sonic Hedgehog (Shh), which is mitogenic for stem cells in the cerebellum, cortex, and in diverse? cancers. We will identify proteoglycans required for Shh- mediated proliferation using a new assay for? mitogenic niches, and we will determine how a glyco code might regulate stem cell propagation. As? the work progresses we will extend our studies to define proteoglycan structures that modulate the? response of stem cells to additional agents such as EGF or FGF family members. These studies will? contribute to the identification of a glyco-code, and will determine mechanisms that maintain ?stemness?.? Such studies can lead to enhanced therapies for disorders from Alzheimers disease to? cancers to stroke.

National Institute of Health (NIH)
Office of The Director, National Institutes of Health (OD)
NIH Director’s Pioneer Award (NDPA) (DP1)
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Special Emphasis Panel (ZGM1-NDPA-G (P2))
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Jones, Warren
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Dana-Farber Cancer Institute
United States
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Persson, Laura; Witt, Rochelle M; Galligan, Meghan et al. (2014) Shh-proteoglycan interactions regulate maturation of olfactory glomerular circuitry. Dev Neurobiol 74:1255-67
Witt, Rochelle M; Hecht, Marie-Lyn; Pazyra-Murphy, Maria F et al. (2013) Heparan sulfate proteoglycans containing a glypican 5 core and 2-O-sulfo-iduronic acid function as Sonic Hedgehog co-receptors to promote proliferation. J Biol Chem 288:26275-88
Zhou, Pengcheng; Alfaro, Jose; Chang, Eun Hyuk et al. (2011) Numb links extracellular cues to intracellular polarity machinery to promote chemotaxis. Dev Cell 20:610-22
Chan, Jennifer A; Balasubramanian, Srividya; Witt, Rochelle M et al. (2009) Proteoglycan interactions with Sonic Hedgehog specify mitogenic responses. Nat Neurosci 12:409-17
Witt, Rochelle M; Galligan, Meghan M; Despinoy, Jennifer R et al. (2009) Olfactory behavioral testing in the adult mouse. J Vis Exp :