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.
Chan
Jennifer A
JA
Neurobiology Department, Harvard Medical School, Boston, Massachusetts, USA.
Balasubramanian
Srividya
S
Witt
Rochelle M
RM
Nazemi
Kellie J
KJ
Choi
Yoojin
Y
Pazyra-Murphy
Maria F
MF
Walsh
Carolyn O
CO
Thompson
Margaret
M
Segal
Rosalind A
RA
D000818:Animals; D000831:Animals, Newborn; D019521:Body Patterning / Q000235:genetics; D001973:Bromodeoxyuridine / Q000378:metabolism; D049109:Cell Proliferation; D002490:Central Nervous System / Q000033:anatomy & histology / Q000196:embryology / Q000254:growth & development; D004622:Embryo, Mammalian; D005343:Fibrinolytic Agents / Q000494:pharmacology; D015870:Gene Expression / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D017261:Glycosylphosphatidylinositols / Q000378:metabolism; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006493:Heparin / Q000494:pharmacology; D006657:Histones / Q000235:genetics / Q000378:metabolism; D020287:In Situ Nick-End Labeling / Q000379:methods; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008938:Mitosis / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D011509:Proteoglycans / Q000378:metabolism*; D013234:Stem Cells / Q000145:classification / Q000502:physiology; D000074290:Zinc Finger Protein Gli3
D005343:Fibrinolytic Agents; C465571:Gli3 protein, mouse; D017261:Glycosylphosphatidylinositols; D053823:Hedgehog Proteins; D006657:Histones; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D011509:Proteoglycans; C465570:Shh protein, mouse; D000074290:Zinc Finger Protein Gli3; D006493:Heparin; D001973:Bromodeoxyuridine