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

doi:10.1038/nn.2287

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

Research output: Contribution to journal › Article › peer-review

67 Scopus citations

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 language	English (US)
Pages (from-to)	409-417
Number of pages	9
Journal	Nature Neuroscience
Volume	12
Issue number	4
DOIs	https://doi.org/10.1038/nn.2287
State	Published - Apr 2009
Externally published	Yes

Funding

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.

Funders	Funder number
Children’s Hospital Mental Retardation and Developmental Disabilities Research Center
Dana Farber Cancer Institute Mahoney Center for Neuro-Oncology
US National Institutes of Health
NIH Office of the Director	DP1OD000839
National Institute of Neurological Disorders and Stroke	R01NS037757
Harvard NeuroDiscovery Center
Musella Foundation For Brain Tumor Research and Information

ASJC Scopus subject areas

General Neuroscience

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10.1038/nn.2287

Cite this

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title = "Proteoglycan interactions with Sonic Hedgehog specify mitogenic responses",

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.",

author = "Chan, \{Jennifer A.\} and Srividya Balasubramanian and Witt, \{Rochelle M.\} and Nazemi, \{Kellie J.\} and Yoojin Choi and Pazyra-Murphy, \{Maria F.\} and Walsh, \{Carolyn O.\} and Margaret Thompson and Segal, \{Rosalind A.\}",

note = "Funding Information: 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{\textquoteright}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{\textquoteright}s Hospital Mental Retardation and Developmental Disabilities Research Center and the Harvard NeuroDiscovery Center.",

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AU - Choi, Yoojin

AU - Pazyra-Murphy, Maria F.

AU - Walsh, Carolyn O.

AU - Thompson, Margaret

AU - Segal, Rosalind A.

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Proteoglycan interactions with Sonic Hedgehog specify mitogenic responses

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