title: Kif3a is necessary for initiation and maintenance of medulloblastoma.
abstract: Medulloblastoma (MB) cells arise from granule neuron precursors (GNPs) that have lost growth control. During normal development, GNPs divide in response to Sonic hedgehog (SHH), a ligand that binds to the patched (PTCH) receptor on GNPs. If one copy of the Ptch gene is lost, as in human Gorlin's syndrome and in Ptch(+/-) mice, MBs may form. Proper transduction of the SHH signal critically depends on primary cilia. Loss of primary cilia results in improper signal reception and failure to properly activate SHH target genes. KIF3a, part of a kinesin motor, is required for formation of primary cilia. Here, we use tamoxifen-induced ablation of Kif3a in GNPs of postnatal Ptch(+/-) mouse cerebella to show that KIF3a is necessary for MB formation. To investigate the importance of primary cilia in established tumors, we deleted Kif3a from cultured cells and from tumor cell grafts. The loss of Kif3a from established tumors led to their growth arrest and regression. MBs behave as if they are addicted to the presence of primary cilia. These results underscore the potential utility of agents that disrupt cilia for the treatment of Hh pathway-related MBs.
authors: Departments of Developmental Biology, Genetics, and Bioengineering, Howard Hughes Medical Institute, Stanford University School of Medicine, Clark Center West W252, 318 Campus Drive, Stanford, CA 94305-5439, USA.
authors: Monique T
authors: MT
authors: Barakat
authors: Eric W
authors: EW
authors: Humke
authors: Matthew P
authors: MP
authors: Scott
mesh_terms: D016475:3T3 Cells; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D002528:Cerebellar Neoplasms / Q000235:genetics / Q000378:metabolism*; D002923:Cilia / Q000502:physiology*; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D016547:Kinesins / Q000235:genetics / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D008527:Medulloblastoma / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology; D060449:Wnt Signaling Pathway; D000075746:Zinc Finger Protein Gli2
chemical_list: D018931:Antineoplastic Agents, Hormonal; C000618551:Gli2 protein, mouse; D053823:Hedgehog Proteins; C490202:Kif3a protein, mouse; D051741:Kruppel-Like Transcription Factors; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; C465570:Shh protein, mouse; D000075746:Zinc Finger Protein Gli2; D013629:Tamoxifen; D016547:Kinesins
references: Cell. 2007 Jun 29;129(7):1255-7
references: 17604715
references: Dev Dyn. 2008 Aug;237(8):2030-8
references: 18488998
references: Neurosurg Focus. 2010 Jan;28(1):E6
references: 20043721
references: J Neurooncol. 2001 Jul;53(3):307-18
references: 11718263
references: Cancer Res. 2008 Mar 15;68(6):1768-76
references: 18339857
references: Trends Neurosci. 1997 Apr;20(4):143-4
references: 9106351
references: Cancer Res. 2010 Jan 15;70(2):762-71
references: 20068162
references: Proc Natl Acad Sci U S A. 1999 Apr 27;96(9):5043-8
references: 10220415
references: PLoS Genet. 2005 Oct;1(4):e53
references: 16254602
references: Gan. 1970 Feb;61(1):17-26
references: 5443436
references: Nat Med. 2009 Sep;15(9):1055-61
references: 19701205
references: Genes Dev. 2001 Dec 1;15(23):3059-87
references: 11731473
references: Genesis. 2001 Oct;31(2):85-94
references: 11668683
references: Nat Cell Biol. 2008 Jan;10(1):70-6
references: 18084282
references: Dev Biol. 2009 Jun 15;330(2):452-60
references: 19371734
references: Science. 1997 Aug 22;277(5329):1109-13
references: 9262482
references: Cell. 1996 Jun 14;85(6):841-51
references: 8681379
references: Genes Dev. 2009 Aug 15;23(16):1910-28
references: 19684112
references: Development. 1999 Jun;126(14):3205-16
references: 10375510
references: J Cell Biol. 2008 Jan 14;180(1):23-9
references: 18180368
references: Dev Biol. 2005 Nov 15;287(2):378-89
references: 16229832
references: Gene Expr Patterns. 2003 Aug;3(4):389-95
references: 12915300
references: Neuron. 1999 Jan;22(1):103-14
references: 10027293
references: Dev Biol. 2008 May 1;317(1):246-59
references: 18353302
references: J Immunol Methods. 1983 Dec 16;65(1-2):55-63
references: 6606682
references: Cancer Cell. 2008 Aug 12;14(2):135-45
references: 18691548
references: Development. 2007 Jun;134(11):2159-69
references: 17507416
references: Proc Natl Acad Sci U S A. 2005 Aug 9;102(32):11325-30
references: 16061793
references: Cancer Cell. 2008 Aug 12;14(2):123-34
references: 18691547
references: Neuron. 2005 Oct 6;48(1):17-24
references: 16202705
references: Science. 2002 Aug 30;297(5586):1559-61
references: 12202832
references: Curr Biol. 1999 Apr 22;9(8):445-8
references: 10226030
references: Clin Cancer Res. 2006 Oct 15;12(20 Pt 1):5924-8
references: 17062662
references: Genes Dev. 2010 Apr 1;24(7):670-82
references: 20360384
references: Science. 2007 Jul 20;317(5836):372-6
references: 17641202
references: Nature. 2005 Oct 13;437(7061):1018-21
references: 16136078
references: Nat Rev Genet. 2010 May;11(5):331-44
references: 20395968
references: Development. 2001 Dec;128(24):5201-12
references: 11748155
references: Nature. 2003 Nov 6;426(6962):83-7
references: 14603322
references: Nat Med. 2009 Sep;15(9):1062-5
references: 19701203
references: J Neurosci. 2007 Sep 5;27(36):9780-9
references: 17804638
references: J Cell Biol. 1994 Jun;125(5):1095-107
references: 7515068
references: Dev Dyn. 2006 Nov;235(11):2991-8
references: 16958097
references: Development. 2005 Jul;132(13):3103-11
references: 15930098
references: Development. 1997 Jan;124(1):113-23
references: 9006072
references: Cancer Res. 1980 Jul;40(7):2142-6
references: 6992981
references: Science. 1996 Jun 14;272(5268):1668-71
references: 8658145
references: Trends Genet. 1997 Jan;13(1):14-21
references: 9009843
references: Development. 1998 Mar;125(5):919-28
references: 9449674