title: Differential modulation of Sonic-hedgehog-induced cerebellar granule cell precursor proliferation by the IGF signaling network.
abstract: The molecular mechanisms regulating organ growth and size remain unclear. Sonic hedgehog (SHH) signaling is a major player in the regulation of cerebellar development: SHH is secreted by Purkinje neurons and acts on the proliferation of granule cell precursors (GCPs) in the external germinal layer. These then become postmitotic and form the internal granular layer but do so in the presence of SHH ligand, begging the question of how the proliferative response to SHH signaling is downregulated in differentiating GCPs. Here, we have determined the precise cellular localization of the expression of insulin-like growth factor (IGF) network components in the developing mouse cerebellum and show that this network modulates the proliferative effects of SHH signaling on GCPs. IGF1 and IGF2 are potent mitogens for GCPs and both synergize with SHH in inducing GCP proliferation. Whereas the proliferative activity of IGF1 or IGF2 on GCPs does not require intact SHH signaling, aspects of SHH activity on GCP proliferation require signaling through the IGF receptor 1. Moreover, we find that 3 of the IGF-binding proteins, IGFBP2, IGFBP3 and IGFBP5, inhibit IGF1/2-induced cell proliferation, whereas IGFBP5 also inhibits SHH-induced GCPs proliferation. This novel function of IGFBP5 that we have uncovered demonstrates the exquisite regulation of SHH signaling by different components of the IGF network.
authors.affiliation: CNRS Institut de Biologie du Développement de Marseille (CNRS Univ. Méditerranée), Campus de Luminy, Marseille, France.
authors.forename: Carla
authors.initials: C
authors.lastname: Fernandez
authors.forename: Valérie M
authors.initials: VM
authors.lastname: Tatard
authors.forename: Nicolas
authors.initials: N
authors.lastname: Bertrand
authors.forename: Nadia
authors.initials: N
authors.lastname: Dahmane
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000378:metabolism* / Q000494:pharmacology; D017403:In Situ Hybridization; D018969:Insulin-Like Growth Factor Binding Proteins / Q000235:genetics / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D053823:Hedgehog Proteins; D018969:Insulin-Like Growth Factor Binding Proteins; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1
references.citation: Trends Neurosci. 1998 Sep;21(9):375-82
references.pmid: 9735945
references.citation: J Biol Chem. 1997 Aug 15;272(33):20572-6
references.pmid: 9252371
references.citation: Neuroscience. 1993 Mar;53(1):251-65
references.pmid: 7682300
references.citation: Development. 1997 Jul;124(13):2537-52
references.pmid: 9216996
references.citation: Nat Rev Neurosci. 2001 Jul;2(7):484-91
references.pmid: 11433373
references.citation: Endocr Rev. 2005 Dec;26(7):916-43
references.pmid: 16131630
references.citation: Development. 2001 Dec;128(24):5201-12
references.pmid: 11748155
references.citation: Cancer Cell. 2004 Sep;6(3):229-40
references.pmid: 15380514
references.citation: J Cell Biol. 1985 Feb;100(2):384-96
references.pmid: 3881455
references.citation: Science. 1997 Aug 22;277(5329):1109-13
references.pmid: 9262482
references.citation: Nat Rev Cancer. 2002 May;2(5):361-72
references.pmid: 12044012
references.citation: Cell. 1996 Jun 14;85(6):841-51
references.pmid: 8681379
references.citation: Development. 2004 Jul;131(13):3159-68
references.pmid: 15197161
references.citation: Cell. 1993 Oct 8;75(1):73-82
references.pmid: 8402902
references.citation: Neuropeptides. 2002 Apr-Jun;36(2-3):209-20
references.pmid: 12359511
references.citation: Development. 2001 Jun;128(11):1971-81
references.pmid: 11493520
references.citation: Genes Dev. 2002 Nov 1;16(21):2743-8
references.pmid: 12414725
references.citation: Neuron. 1999 Jan;22(1):103-14
references.pmid: 10027293
references.citation: J Biol Chem. 2000 Sep 15;275(37):28341-4
references.pmid: 10884376
references.citation: Development. 2008 Oct;135(19):3291-300
references.pmid: 18755774
references.citation: Mol Endocrinol. 1990 May;4(5):773-8
references.pmid: 2177145
references.citation: Annu Rev Neurosci. 1995;18:385-408
references.pmid: 7605067
references.citation: Am J Pathol. 2005 Apr;166(4):1153-62
references.pmid: 15793295
references.citation: Development. 2006 May;133(9):1811-21
references.pmid: 16571625
references.citation: Brain Res Mol Brain Res. 2000 Feb 22;75(2):185-97
references.pmid: 10686339
references.citation: Prog Growth Factor Res. 1995;6(2-4):437-45
references.pmid: 8817688
references.citation: Nature. 2002 Jan 24;415(6870):436-42
references.pmid: 11807556
references.citation: Endocr Rev. 2002 Dec;23(6):824-54
references.pmid: 12466191
references.citation: Development. 2005 May;132(10):2425-39
references.pmid: 15843415
references.citation: Nat Rev Neurosci. 2002 Jan;3(1):24-33
references.pmid: 11823802
references.citation: Development. 2004 Jan;131(1):217-28
references.pmid: 14660435
references.citation: J Neurochem. 1998 Mar;70(3):1327-30
references.pmid: 9489757
references.citation: Proc Natl Acad Sci U S A. 2004 Feb 17;101(7):2076-81
references.pmid: 14764897
references.citation: Science. 2002 Aug 30;297(5586):1559-61
references.pmid: 12202832
references.citation: Curr Biol. 1999 Apr 22;9(8):445-8
references.pmid: 10226030
references.citation: Cell. 1993 Oct 8;75(1):59-72
references.pmid: 8402901
references.citation: Nature. 1990 May 3;345(6270):78-80
references.pmid: 2330056
references.citation: Science. 1997 Jan 31;275(5300):661-5
references.pmid: 9005851
references.citation: Development. 1999 Oct;126(20):4431-40
references.pmid: 10498679
references.citation: Development. 2001 May;128(9):1481-92
references.pmid: 11290288
references.citation: Neuron. 1991 May;6(5):705-15
references.pmid: 2025426
references.citation: J Neurosci. 1993 Dec;13(12):5092-104
references.pmid: 7504720
references.citation: Neuron. 2001 Aug 30;31(4):557-68
references.pmid: 11545715
references.citation: Growth Regul. 1993 Mar;3(1):5-8
references.pmid: 7683529
references.citation: Mol Neurobiol. 1996 Dec;13(3):227-55
references.pmid: 8989772
references.citation: Development. 1999 Jun;126(14):3089-100
references.pmid: 10375501
references.citation: Prog Neurobiol. 2004 Apr;72(5):295-339
references.pmid: 15157725
references.citation: Development. 2003 Jan;130(1):15-28
references.pmid: 12441288
references.citation: J Neurosci. 1996 Dec 1;16(23):7649-60
references.pmid: 8922421
references.citation: Cell Mol Life Sci. 2000 Jun;57(6):932-42
references.pmid: 10950308
references.citation: Cancer Res. 2003 Dec 15;63(24):8912-21
references.pmid: 14695208
references.citation: Genes Dev. 2001 Dec 1;15(23):3059-87
references.pmid: 11731473
references.citation: J Biol Chem. 2002 Apr 5;277(14):12053-60
references.pmid: 11821401
references.citation: J Neurosci. 2002 Nov 1;22(21):9244-54
references.pmid: 12417650
references.citation: Development. 2002 May;129(9):2223-32
references.pmid: 11959830
references.citation: Trends Cell Biol. 2003 Feb;13(2):79-85
references.pmid: 12559758
references.citation: J Neurosci. 2004 Mar 31;24(13):3402-12
references.pmid: 15056720
references.citation: Anat Embryol (Berl). 2003 Jul;207(1):73-84
references.pmid: 12743812
references.citation: Brain Res Dev Brain Res. 1996 Aug 20;95(1):44-54
references.pmid: 8873975
references.citation: Dev Biol. 2004 Jun 15;270(2):393-410
references.pmid: 15183722
references.citation: Mol Cell Neurosci. 1995 Jun;6(3):230-51
references.pmid: 7496629
references.citation: Science. 1996 Jun 14;272(5268):1668-71
references.pmid: 8658145
references.citation: Proc Natl Acad Sci U S A. 1988 Jan;85(1):141-5
references.pmid: 3422410
references.citation: Nat Med. 1998 May;4(5):619-22
references.pmid: 9585239