Proteoglycan interactions with Sonic Hedgehog specify mitogenic responses

Jennifer A. Chan, Srividya Balasubramanian, Rochelle M. Witt, Kellie J. Nazemi, Yoojin Choi, Maria F. Pazyra-Murphy, Carolyn O. Walsh, Margaret Thompson, Rosalind A. Segal

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Abstract

Sonic Hedgehog (Shh) has dual roles in vertebrate development, promoting progenitor cell proliferation and inducing tissue patterning. We found that the mitogenic and patterning functions of Shh can be uncoupled from one another. Using a genetic approach to selectively inhibit Shh-proteoglycan interactions in a mouse model, we found that binding of Shh to proteoglycans was required for proliferation of neural stem/precursor cells, but not for tissue patterning. Shh-proteoglycan interactions regulated both spatial and temporal features of Shh signaling. Proteoglycans localized Shh to specialized mitogenic niches and also acted at the single-cell level to regulate the duration of Shh signaling, thereby promoting a gene expression program that is important for cell division. Because activation of the Shh pathway is a feature of diverse human cancers, selective stimulation of proliferation by Shh-proteoglycan interactions may also figure prominently in neoplastic growth.

Original languageEnglish (US)
Pages (from-to)409-417
Number of pages9
JournalNature Neuroscience
Volume12
Issue number4
DOIs
StatePublished - Apr 1 2009

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ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Chan, J. A., Balasubramanian, S., Witt, R. M., Nazemi, K. J., Choi, Y., Pazyra-Murphy, M. F., Walsh, C. O., Thompson, M., & Segal, R. A. (2009). Proteoglycan interactions with Sonic Hedgehog specify mitogenic responses. Nature Neuroscience, 12(4), 409-417. https://doi.org/10.1038/nn.2287