A gradient of Gli activity mediates graded Sonic Hedgehog signaling in the neural tube.
During development, many signaling factors behave as morphogens, long-range signals eliciting different cellular responses according to their concentration. In ventral regions of the spinal cord, Sonic Hedgehog (Shh) is such a signal and controls the emergence, in precise spatial order, of distinct neuronal subtypes. The Gli family of transcription factors plays a central role in this process. Here we demonstrate that a gradient of Gli activity is sufficient to mediate, cell-autonomously, the full range of Shh responses in the neural tube. The incremental two- to threefold changes in Shh concentration, which determine alternative neuronal subtypes, are mimicked by similar small changes in the level of Gli activity, indicating that a gradient of Gli activity represents the intracellular correlate of graded Shh signaling. Moreover, our analysis suggests that cells integrate the level of signaling over time, consistent with the idea that signal duration, in addition to signal strength, is an important parameter controlling dorsal-ventral patterning. Together, these data indicate that Shh signaling is transduced, without amplification, into a gradient of Gli activity that orchestrates patterning of the ventral neural tube.
Stamataki
Despina
D
Developmental Neurobiology, National Institute for Medical Research, Mill Hill, London, NW7 1AA, United Kingdom.
Ulloa
Fausto
F
Tsoni
Stavroula V
SV
Mynett
Anita
A
Briscoe
James
J
D000818:Animals; D002642:Chick Embryo; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D053823:Hedgehog Proteins; D006801:Humans; D009474:Neurons / Q000502:physiology; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D038081:Organogenesis / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D013116:Spinal Cord / Q000196:embryology*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000071676:Zinc Finger Protein GLI1
D053823:Hedgehog Proteins; D015513:Oncogene Proteins; C509239:SHH protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1
Cell. 2000 Feb 18;100(4):423-34
10693759
Development. 1993 Dec;119(4):1203-15
8306883
Mech Dev. 1998 Mar;72(1-2):77-88
9533954
Cell. 2001 Jun 1;105(5):599-612
11389830
J Morphol. 1951 Jan;88(1):49-92
24539719
Cell. 1993 Mar 12;72(5):741-52
8453668
Curr Opin Cell Biol. 1996 Apr;8(2):231-8
8791421
Development. 2002 Jul;129(14):3411-9
12091311
Dev Genes Evol. 2000 Jan;210(1):47-50
10603087
Nature. 1999 Apr 15;398(6728):622-7
10217145
Genes Dev. 2002 Nov 15;16(22):2849-64
12435628
Proc Natl Acad Sci U S A. 1999 Jun 8;96(12):6791-6
10359791
Development. 2000 Apr;127(8):1593-605
10725236
Cell. 2004 Aug 20;118(4):517-28
15315763
Neuron. 2001 Feb;29(2):367-84
11239429
Gene. 1991 Dec 15;108(2):193-9
1660837
Development. 2003 Apr;130(8):1549-64
12620981
Cell. 1986 Jun 6;45(5):721-32
3518947
Dev Biol. 2001 Aug 15;236(2):364-86
11476578
Dev Biol. 2001 Nov 1;239(1):15-29
11784016
Cell. 1999 Jun 25;97(7):903-15
10399918
Mol Cell. 2001 Jun;7(6):1279-91
11430830
Development. 2002 Oct;129(20):4753-61
12361967
Cold Spring Harb Symp Quant Biol. 1997;62:451-66
9598380
Cell. 2004 Aug 20;118(4):505-16
15315762
Cell. 1997 Jul 11;90(1):169-80
9230312
Nat Genet. 2000 Oct;26(2):216-20
11017081
Genes Dev. 1992 Aug;6(8):1518-30
1644293
Nat Neurosci. 2000 Jan;3(1):41-6
10607393
Cell. 1995 Sep 22;82(6):969-79
7553857
Development. 1998 Jun;125(12):2203-12
9584120
Histochemistry. 1993 Dec;100(6):431-40
7512949
Development. 2003 Dec;130(23):5681-93
14522876
Dev Cell. 2004 Jan;6(1):103-15
14723851
Mol Cell. 2003 Apr;11(4):915-26
12718878
Nat Rev Genet. 2000 Oct;1(1):20-9
11262869
Dev Biol. 2002 Aug 15;248(2):356-68
12167410
Nature. 2001 Oct 25;413(6858):797-803
11677596
Neuron. 2001 Sep 13;31(5):743-55
11567614
Cell. 1996 Jun 28;85(7):951-61
8674123
Genes Dev. 2001 Dec 1;15(23):3059-87
11731473
Cell. 1996 Nov 15;87(4):661-73
8929535
Nat Neurosci. 2000 Oct;3(10):979-85
11017169
Development. 1999 Sep;126(17):3915-24
10433919
Development. 2001 Jun;128(12):2385-96
11493557
EMBO Rep. 2003 Aug;4(8):761-5
12897799
Trends Genet. 2000 Jan;16(1):40-4
10637630
Curr Opin Neurobiol. 2001 Feb;11(1):43-9
11179871
Cell. 2002 Nov 27;111(5):687-701
12464180
Curr Biol. 2003 Jul 15;13(14):1169-81
12867027
Development. 1998 Aug;125(15):2759-70
9655799
Cell. 1993 May 21;73(4):673-86
8500163
Nature. 1999 Feb 18;397(6720):617-21
10050855
Development. 2004 Dec;131(23):5959-69
15539490
Cell. 2001 Mar 23;104(6):861-73
11290324
Neuron. 2003 Aug 28;39(5):749-65
12948443
Trends Genet. 1996 Sep;12(9):359-64
8855666
Dev Biol. 2002 Jun 1;246(1):57-67
12027434
Dev Biol. 2004 Nov 1;275(1):143-57
15464578
Development. 2000 Oct;127(19):4293-301
10976059
Genes Dev. 2002 Nov 15;16(22):2865-78
12435629
Development. 2001 Dec;128(24):5161-72
11748151
Development. 1998 Jul;125(14):2533-43
9636069
Nat Neurosci. 2003 Nov;6(11):1162-8
14517545
Dev Biol. 1996 Nov 25;180(1):273-83
8948590
Mol Cell Neurosci. 1995 Apr;6(2):106-21
7551564
Development. 1997 Jul;124(13):2537-52
9216996
Development. 2004 Aug;131(15):3593-604
15215207
Neuron. 1999 Aug;23(4):659-74
10482234
Development. 1995 Jun;121(6):1755-68
7600991
Neuron. 2002 May 16;34(4):551-62
12062039
Curr Opin Genet Dev. 2003 Oct;13(5):513-21
14550418
Neuron. 2001 Sep 13;31(5):773-89
11567616
Development. 1995 May;121(5):1321-32
7540531
Dev Biol. 1994 Apr;162(2):402-13
8150204
J Biol Chem. 1999 Mar 19;274(12):8143-52
10075717
Neuron. 2003 Sep 25;40(1):81-95
14527435
Development. 1997 Apr;124(7):1313-22
9118802
Cell. 1998 Oct 2;95(1):67-80
9778248
Cell. 2000 May 12;101(4):435-45
10830170
Neuron. 2003 Sep 25;40(1):65-79
14527434