Nmyc upregulation by sonic hedgehog signaling promotes proliferation in developing cerebellar granule neuron precursors.
Hedgehog pathway activation is required for expansion of specific neuronal precursor populations during development and is etiologic in the human cerebellar tumor, medulloblastoma. We report that sonic hedgehog (Shh) signaling upregulates expression of the proto-oncogene Nmyc in cultured cerebellar granule neuron precursors (CGNPs) in the absence of new protein synthesis. The temporal-spatial expression pattern of Nmyc, but not other Myc family members, precisely coincides with regions of hedgehog proliferative activity in the developing cerebellum and is observed in medulloblastomas of Patched (Ptch) heterozygous mice. Overexpression of Nmyc promotes cell-autonomous G(1) cyclin upregulation and CGNP proliferation independent of Shh signaling. Furthermore, Myc antagonism in vitro significantly decreases proliferative effects of Shh in cultured CGNPs. Together, these findings identify Nmyc as a direct target of the Shh pathway that functions to regulate cell cycle progression in cerebellar granule neuron precursors.
Kenney
Anna Marie
AM
Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
Cole
Michael D
MD
Rowitch
David H
DH
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D002528:Cerebellar Neoplasms / Q000235:genetics / Q000378:metabolism; D002531:Cerebellum / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins; D006579:Heterozygote; D047908:Intracellular Signaling Peptides and Proteins; D008527:Medulloblastoma / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D011956:Receptors, Cell Surface; D013234:Stem Cells / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D014704:Veratrum Alkaloids / Q000494:pharmacology
D051792:Basic Helix-Loop-Helix Proteins; D019938:Cyclin D1; D053823:Hedgehog Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc; D011956:Receptors, Cell Surface; D015534:Trans-Activators; D014157:Transcription Factors; D014704:Veratrum Alkaloids; C500943:Atoh1 protein, mouse; C000715470:MAS1 protein, human; C000606236:PTCH1 protein, human; C000606240:Ptch1 protein, mouse; C465570:Shh protein, mouse; C000541:cyclopamine