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Proteoglycan interactions with Sonic Hedgehog specify mitogenic responses.

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.

Pubmed ID: 19287388

Authors

  • Chan JA
  • Balasubramanian S
  • Witt RM
  • Nazemi KJ
  • Choi Y
  • Pazyra-Murphy MF
  • Walsh CO
  • Thompson M
  • Segal RA

Journal

Nature neuroscience

Publication Data

April 26, 2009

Associated Grants

  • Agency: NIH HHS, Id: DP1 OD000839
  • Agency: NIH HHS, Id: DP1 OD000839-01
  • Agency: NINDS NIH HHS, Id: R01 NS037757
  • Agency: NINDS NIH HHS, Id: R01 NS037757-09

Mesh Terms

  • Animals
  • Animals, Newborn
  • Body Patterning
  • Bromodeoxyuridine
  • Cell Proliferation
  • Central Nervous System
  • Embryo, Mammalian
  • Fibrinolytic Agents
  • Gene Expression
  • Gene Expression Regulation, Developmental
  • Glycosylphosphatidylinositols
  • Hedgehog Proteins
  • Heparin
  • Histones
  • In Situ Nick-End Labeling
  • Kruppel-Like Transcription Factors
  • Mice
  • Mice, Transgenic
  • Mitosis
  • Mutation
  • Nerve Tissue Proteins
  • Protein Binding
  • Proteoglycans
  • Stem Cells