title: Lin28B and Let-7 in the Control of Sympathetic Neurogenesis and Neuroblastoma Development.
abstract: The RNA binding protein Lin28B is expressed in developing tissues and sustains stem and progenitor cell identity as a negative regulator of the Let-7 family of microRNAs, which induces differentiation. Lin28B is activated in neuroblastoma (NB), a childhood tumor in sympathetic ganglia and adrenal medulla. Forced expression of Lin28B in embryonic mouse sympathoadrenal neuroblasts elicits postnatal NB formation. However, the normal function of Lin28B in the development of sympathetic neurons and chromaffin cells and the mechanisms involved in Lin28B-induced tumor formation are unclear. Here, we demonstrate a mirror-image expression of Lin28B and Let-7a in developing chick sympathetic ganglia. Lin28B expression is not restricted to undifferentiated progenitor cells but, is observed in proliferating noradrenergic neuroblasts. Lin28 knockdown in cultured sympathetic neuroblasts decreases proliferation, whereas Let-7 inhibition increases the proportion of neuroblasts in the cell cycle. Lin28B overexpression enhances proliferation, but only during a short developmental period, and it does not reduce Let-7a. Effects of in vivo Lin28B overexpression were analyzed in the LSL-Lin28B(DBHiCre) mouse line. Sympathetic ganglion and adrenal medulla volume and the expression level of Let-7a were not altered, although Lin28B expression increased by 12- to 17-fold. In contrast, Let-7a expression was strongly reduced in LSL-Lin28B(DbhiCre) NB tumor tissue. These data demonstrate essential functions for endogenous Lin28 and Let-7 in neuroblast proliferation. However, Lin28B overexpression neither sustains neuroblast proliferation nor affects let-7 expression. Thus, in contrast to other pediatric tumors, Lin28B-induced NB is not due to expansion of proliferating embryonic neuroblasts, and Let-7-independent functions are implicated during initial NB development.
  
  
  CONCLUSIONS
  Lin28A/B proteins are highly expressed in early development and maintain progenitor cells by blocking the biogenesis and differentiation function of Let-7 microRNAs. Lin28B is aberrantly upregulated in the childhood tumor neuroblastoma (NB). NB develops in sympathetic ganglia and adrenal medulla and is elicited by forced Lin28B expression. We demonstrate that Lin28A/B and Let-7 are essential for sympathetic neuroblast proliferation during normal development. Unexpectedly, Lin28B upregulation in a mouse model does not affect neuroblast proliferation, ganglion size, and Let-7 expression during early postnatal development. Lin28B-induced NB, in contrast to other pediatric cancers, does not evolve from neuroblasts that continue to divide and involves Let-7-independent functions during initial development.
authors.affiliation: Developmental Neurobiology, Max Planck Institute for Brain Research, 60438 Frankfurt am Main, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Hennchen
authors.affiliation: Developmental Neurobiology, Max Planck Institute for Brain Research, 60438 Frankfurt am Main, Germany, Institute of Clinical Neuroanatomy, Goethe University of Frankfurt, 60590 Frankfurt am Main, Germany, Ernst Strüngmann Institute, 60528 Frankfurt am Main, Germany.
authors.forename: Jutta
authors.initials: J
authors.lastname: Stubbusch
authors.affiliation: Developmental Neurobiology, Max Planck Institute for Brain Research, 60438 Frankfurt am Main, Germany.
authors.forename: Ikram
authors.initials: I
authors.lastname: Abarchan-El Makhfi
authors.affiliation: Developmental Neurobiology, Max Planck Institute for Brain Research, 60438 Frankfurt am Main, Germany, Institute of Clinical Neuroanatomy, Goethe University of Frankfurt, 60590 Frankfurt am Main, Germany, Ernst Strüngmann Institute, 60528 Frankfurt am Main, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Kramer
authors.affiliation: Institute of Clinical Neuroanatomy, Goethe University of Frankfurt, 60590 Frankfurt am Main, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Deller
authors.affiliation: Unité Institut National de la Santé et de la Recherche Médicale, U830, Centre de Recherche Institut Curie, 75248 Paris Cedex 05, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Pierre-Eugene
authors.affiliation: Unité Institut National de la Santé et de la Recherche Médicale, U830, Centre de Recherche Institut Curie, 75248 Paris Cedex 05, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Janoueix-Lerosey
authors.affiliation: Unité Institut National de la Santé et de la Recherche Médicale, U830, Centre de Recherche Institut Curie, 75248 Paris Cedex 05, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Delattre
authors.affiliation: Developmental Neurobiology, Max Planck Institute for Brain Research, 60438 Frankfurt am Main, Germany, Institute of Clinical Neuroanatomy, Goethe University of Frankfurt, 60590 Frankfurt am Main, Germany, Ernst Strüngmann Institute, 60528 Frankfurt am Main, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Ernsberger
authors.affiliation: Department of Pediatric Oncology and Haematology, Children's Hospital Essen, 45122 Essen, Germany, and.
authors.forename: Johannes B
authors.initials: JB
authors.lastname: Schulte
authors.affiliation: Developmental Neurobiology, Max Planck Institute for Brain Research, 60438 Frankfurt am Main, Germany, Institute of Clinical Neuroanatomy, Goethe University of Frankfurt, 60590 Frankfurt am Main, Germany, Ernst Strüngmann Institute, 60528 Frankfurt am Main, Germany, hermann.rohrer@brain.mpg.de.
authors.forename: Hermann
authors.initials: H
authors.lastname: Rohrer
mesh_terms: D000311:Adrenal Glands / Q000378:metabolism; D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology*; D049109:Cell Proliferation; D002642:Chick Embryo; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology; D005728:Ganglia, Sympathetic / Q000473:pathology; D051379:Mice; D057507:Mice, 129 Strain; D035683:MicroRNAs / Q000235:genetics* / Q000502:physiology; D009447:Neuroblastoma / Q000235:genetics* / Q000473:pathology*; D009473:Neuronal Plasticity / Q000235:genetics / Q000502:physiology; D016601:RNA-Binding Proteins; D013234:Stem Cells / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000254:growth & development* / Q000502:physiology
chemical_list: D004268:DNA-Binding Proteins; C570876:Lin28b protein, mouse; D035683:MicroRNAs; D016601:RNA-Binding Proteins; C542687:mirnlet7 microRNA, mouse
keywords: Let-7; Lin28; neuroblastoma; neurogenesis; proliferation; sympathetic