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Proteoglycan interactions with Sonic Hedgehog specify mitogenic responses

Nature Neuroscience volume 12, pages 409–417 (2009)Cite this article

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.

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Figure 1: ShhAla specifically alters proteoglycan binding.
Figure 2: ShhAla/Ala and ShhAla/− mice show defects in growth, but show normal patterning.
Figure 3: Reduced proliferation of ShhAla/Ala cerebellar granule precursors is seen in the EGL of developing mice.
Figure 4: Embryonic and adult neural stem/precursor proliferation is reduced in ShhAla/Ala mice.
Figure 5: ShhAla cannot specify a mitogenic niche.
Figure 6: Shh-proteoglycan interactions promote proliferation in dissociated cell cultures of GCPs, but are not needed for survival.
Figure 7: Shh-proteoglycan interactions modulate transcriptional activity through the regulation of Gli2 isoforms and signaling kinetics.
Figure 8: Proteoglycan interactions modulate Shh perdurance and differentially affect Shh-dependent gene expression.

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Acknowledgements

We thank J. Despinoy for excellent assistance, C. Stiles, D. Rowitch, M. Greenberg and members of the Segal laboratory for helpful discussions, and D. Rowitch, Q. Ma, P. Chuang, D. Paul, S. O'Gorman, P. Silver and A. McMahon for reagents. This work was supported by the US National Institutes of Health (J.A.C., R.A.S. and S.B.), the Dana Farber Cancer Institute Mahoney Center for Neuro-Oncology (J.A.C.), the Musella Foundation (K.J.N.), the Quan Fellowship (R.M.W.), the Children's Hospital Mental Retardation and Developmental Disabilities Research Center and the Harvard NeuroDiscovery Center.

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Author notes

  1. Jennifer A Chan, Kellie J Nazemi & Yoojin Choi

    Present address: Present addresses: Department of Pathology & Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada (J.A.C.), Division of Pediatric Hematology/Oncology, Doernbecher Children's Hospital, Oregon Health & Science University, Portland, Oregon, USA (K.J.N.) and Science Department, Phillips Exeter Academy, Exeter, New Hampshire, USA (Y.C.).,

  2. Jennifer A Chan, Srividya Balasubramanian and Rochelle M Witt: These authors contributed equally to this work.

Authors and Affiliations

  1. Neurobiology Department, Harvard Medical School, Boston, Massachusetts, USA

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

  2. Pediatric Oncology Department, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

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

  3. Pathology Department, Brigham and Women's Hospital, Boston, Massachusetts, USA

    Jennifer A Chan

  4. Neurology Department, Children's Hospital, Boston, Massachusetts, USA

    Margaret Thompson

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Rosalind A Segal receives a research grant and a consulting fee from Novartis for studies on the Hedgehog pathway and cancer.

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Chan, J., Balasubramanian, S., Witt, R. et al. Proteoglycan interactions with Sonic Hedgehog specify mitogenic responses. Nat Neurosci 12, 409–417 (2009). https://doi.org/10.1038/nn.2287

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