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PMID:19124651

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Citation

Wall, DS, Mears, AJ, McNeill, B, Mazerolle, C, Thurig, S, Wang, Y, Kageyama, R and Wallace, VA (2009) Progenitor cell proliferation in the retina is dependent on Notch-independent Sonic hedgehog/Hes1 activity. J. Cell Biol. 184:101-12

Abstract

Sonic hedgehog (Shh) is an indispensable, extrinsic cue that regulates progenitor and stem cell behavior in the developing and adult mammalian central nervous system. Here, we investigate the link between the Shh signaling pathway and Hes1, a classical Notch target. We show that Shh-driven stabilization of Hes1 is independent of Notch signaling and requires the Shh effector Gli2. We identify Gli2 as a primary mediator of this response by showing that Gli2 is required for Hh (Hedgehog)-dependent up-regulation of Hes1. We also show using chromatin immunoprecipitation that Gli2 binds to the Hes1 promoter, which suggests that Hes1 is a Hh-dependent direct target of Gli2 signaling. Finally, we show that Shh stimulation of progenitor proliferation and cell diversification requires Gli2 and Hes1 activity. This paper is the first demonstration of the mechanistic and functional link between Shh, Gli, and Hes1 in the regulation of progenitor cell behavior.

Links

PubMed PMC2615087 Online version:10.1083/jcb.200805155

Keywords

Animals; Basic Helix-Loop-Helix Transcription Factors/metabolism; Basic Helix-Loop-Helix Transcription Factors/physiology; Cell Differentiation; Cell Proliferation; Hedgehog Proteins/metabolism; Hedgehog Proteins/physiology; Homeodomain Proteins/metabolism; Homeodomain Proteins/physiology; Immunoglobulin J Recombination Signal Sequence-Binding Protein/metabolism; Kruppel-Like Transcription Factors/metabolism; Mice; Mice, Transgenic; Protein Structure, Tertiary; RNA, Messenger/metabolism; Receptors, Notch/chemistry; Receptors, Notch/metabolism; Receptors, Notch/physiology; Repressor Proteins/metabolism; Retina/cytology; Retina/growth & development; Signal Transduction; Stem Cells/cytology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:SUH

acts_upstream_of_or_within

GO:0007219: Notch signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(EMAPA:17168)

Seeded From UniProt

complete

MOUSE:HES1

acts_upstream_of_or_within

GO:0007224: smoothened signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

  • occurs_in:(EMAPA:17168)

Seeded From UniProt

complete

MOUSE:GLI1

acts_upstream_of_or_within

GO:0007224: smoothened signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

  • occurs_in:(EMAPA:17168)

Seeded From UniProt

complete

MOUSE:SMO

acts_upstream_of_or_within

GO:0008284: positive regulation of cell population proliferation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • regulates_o_occurs_in:(EMAPA:17168)

Seeded From UniProt

complete

MOUSE:SMO

acts_upstream_of_or_within

GO:0050821: protein stabilization

ECO:0000314: direct assay evidence used in manual assertion

P

  • occurs_in:(EMAPA:17168)

Seeded From UniProt

complete

MOUSE:HES5

acts_upstream_of_or_within

GO:0007224: smoothened signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

  • occurs_in:(EMAPA:17168)

Seeded From UniProt

complete

MOUSE:GLI2

acts_upstream_of_or_within

GO:0007224: smoothened signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1857509

P

  • occurs_in:(EMAPA:17168)

Seeded From UniProt

complete

MOUSE:GLI2

acts_upstream_of_or_within

GO:0007224: smoothened signaling pathway

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:95727

P

  • occurs_in:(EMAPA:17168)

Seeded From UniProt

complete

MOUSE:GLI2

enables

GO:0000976: transcription cis-regulatory region binding

ECO:0000314: direct assay evidence used in manual assertion

F

  • has_input:(MGI:MGI:104853)

Seeded From UniProt

complete

MOUSE:GLI2

acts_upstream_of_or_within

GO:0007224: smoothened signaling pathway

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:95727

P

occurs_in:(EMAPA:17168)

Seeded From UniProt

complete

MOUSE:GLI2

acts_upstream_of_or_within

GO:0007224: smoothened signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1857509

P

occurs_in:(EMAPA:17168)

Seeded From UniProt

complete

MOUSE:GLI2

enables

GO:0044212: transcription regulatory region DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

has_participant:(MGI:MGI:104853)

Seeded From UniProt

complete

MOUSE:SMO

acts_upstream_of_or_within

GO:0050821: protein stabilization

ECO:0000314: direct assay evidence used in manual assertion

P

occurs_in:(EMAPA:17168)

Seeded From UniProt

complete

MOUSE:SMO

acts_upstream_of_or_within

GO:0008284: positive regulation of cell population proliferation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

regulates_o_occurs_in:(EMAPA:17168)

Seeded From UniProt

complete

MOUSE:GLI1

acts_upstream_of_or_within

GO:0007224: smoothened signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

occurs_in:(EMAPA:17168)

Seeded From UniProt

complete


See also

References

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