Sonic hedgehog-associated medulloblastoma arising from the cochlear nuclei of the brainstem

被引:61
作者
Grammel, Daniel [1 ]
Warmuth-Metz, Monika [2 ]
von Bueren, Andre O. [3 ]
Kool, Marcel [4 ]
Pietsch, Torsten [5 ]
Kretzschmar, Hans A. [1 ]
Rowitch, David H. [6 ,7 ,8 ]
Rutkowski, Stefan [3 ]
Pfister, Stefan M. [4 ,9 ]
Schueller, Ulrich [1 ]
机构
[1] Univ Munich, Ctr Neuropathol, D-81377 Munich, Germany
[2] Univ Wurzburg, Dept Neuroradiol, Wurzburg, Germany
[3] Univ Med Ctr Hamburg Eppendorf, Dept Pediat Hematol & Oncol, Hamburg, Germany
[4] German Canc Res Ctr, Div Mol Genet, D-6900 Heidelberg, Germany
[5] Univ Bonn, Inst Neuropathol, Bonn, Germany
[6] Univ Calif San Francisco, Eli & Edythe Broad Inst Regenerat Med & Stem Cell, San Francisco, CA 94143 USA
[7] Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA 94143 USA
[8] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA
[9] Heidelberg Univ, Dept Pediat Oncol Hematol & Immunol, Heidelberg, Germany
关键词
Medulloblastoma; Sonic hedgehog; Origin; Brainstem; Cochlear nuclei; RHOMBIC-LIP; GRANULE CELLS; EXPRESSION; SUBTYPES; MOUSE; MICE; MUTATIONS; FEATURES; MATH1;
D O I
10.1007/s00401-012-0961-0
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
Medulloblastoma is a malignant brain tumor of childhood that comprises at least four molecularly distinct subgroups. We have previously described that cerebellar granule neuron precursors may give rise to the subgroup with a molecular fingerprint of Sonic hedgehog (Shh) signaling. Other recent data indicate that precursor cells within the dorsal brain stem may serve as cellular origins for Wnt-associated medulloblastomas. To see whether Shh-associated medulloblastomas are also able to develop in the dorsal brainstem, we analyzed two lines of transgenic mice with constitutive Shh signaling in hGFAP- and Math1-positive brainstem precursor populations, respectively. Our results show that in both of these lines, medulloblastomas arise from granule neuron precursors of the cochlear nuclei, a derivative of the auditory lower rhombic lip. This region is distinct from derivatives of precerebellar lower rhombic lip where medulloblastomas arise in mice with constitutive-active Wnt signaling. With respect to their histology and the expression of appropriate markers, Shh tumors from the murine cochlear nuclei perfectly resemble human Shh-associated medulloblastomas. Moreover, we find that in a series of 63 human desmoplastic medulloblastomas, 21 (33%) have a very close contact to the cochlear nuclei on MR imaging. In conclusion, we demonstrate that precursors of the murine rhombic lip, which either develop into cerebellar or into cochlear granule neurons, may give rise to Shh-associated medulloblastoma, and this has important implications for the cellular origin of human medulloblastomas.
引用
收藏
页码:601 / 614
页数:14
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