An integrated approach identifies Nhlh1 and Insm1 as Sonic Hedgehog-regulated genes in developing cerebellum and medulloblastoma.

Medulloblastoma (MB) is the most common malignant brain tumor of childhood arising from deregulated cerebellar development. Sonic Hedgehog (Shh) pathway plays a critical role in cerebellar development and its aberrant expression has been identified in MB. Gene expression profiling of cerebella from 1- to 14-day-old mice unveiled a cluster of genes whose expression correlates with the levels of Hedgehog (HH) activity. From this cluster, we identified Insm1 and Nhlh1/NSCL1 as novel HH targets induced by Shh treatment in cultured cerebellar granule cell progenitors. Nhlh1 promoter was found to be bound and activated by Gli1 transcription factor. Remarkably, the expression of these genes is also upregulated in mouse and human HH-dependent MBs, suggesting that they may be either a part of the HH-induced tumorigenic process or a specific trait of HH-dependent tumor cells.

[1]  J. Altman,et al.  Development of the precerebellar nuclei in the rat: III. The posterior precerebellar extramural migratory stream and the lateral reticular and external cuneate nuclei , 1987, The Journal of comparative neurology.

[2]  K. Kinzler,et al.  The GLI gene encodes a nuclear protein which binds specific sequences in the human genome , 1990, Molecular and cellular biology.

[3]  M. de Silva,et al.  A novel human insulinoma-associated cDNA, IA-1, encodes a protein with "zinc-finger" DNA-binding motifs. , 1992, The Journal of biological chemistry.

[4]  A. Green,et al.  Molecular characterization of NSCL, a gene encoding a helix-loop-helix protein expressed in the developing nervous system. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[5]  M. Lan,et al.  IA-1, a new marker for neuroendocrine differentiation in human lung cancer cell lines. , 1993, Cancer research.

[6]  Michael Dean,et al.  Mutations of the Human Homolog of Drosophila patched in the Nevoid Basal Cell Carcinoma Syndrome , 1996, Cell.

[7]  K. Chada,et al.  Expression of the helix‐loop‐helix genes Id‐1 and NSCL‐1 during cerebellar development , 1997, Developmental dynamics : an official publication of the American Association of Anatomists.

[8]  P. Rakic,et al.  Distinct Modes of Neuronal Migration in Different Domains of Developing Cerebellar Cortex , 1998, The Journal of Neuroscience.

[9]  L. Wojnowski,et al.  Rhabdomyosarcomas and radiation hypersensitivity in a mouse model of Gorlin syndrome , 1998, Nature Medicine.

[10]  M. Uittenbogaard,et al.  Expression of the bHLH gene NSCL‐1 suggests a role in regulating cerebellar granule cell growth and differentiation , 1999, Journal of neuroscience research.

[11]  A. Copp,et al.  Sequence and expression analysis of Nhlh1: a basic helix-loop-helix gene implicated in neurogenesis. , 1999, Developmental genetics.

[12]  C. Murre,et al.  Helix-Loop-Helix Proteins: Regulators of Transcription in Eucaryotic Organisms , 2000, Molecular and Cellular Biology.

[13]  M. Scott,et al.  The developmental biology of brain tumors. , 2001, Annual review of neuroscience.

[14]  M. Nóbrega,et al.  Gene Expression Profiling Leads to Identification of GLI1-binding Elements in Target Genes and a Role for Multiple Downstream Pathways in GLI1-induced Cell Transformation* , 2002, The Journal of Biological Chemistry.

[15]  P. Sánchez,et al.  Gli and hedgehog in cancer: tumours, embryos and stem cells , 2002, Nature Reviews Cancer.

[16]  T. Poggio,et al.  Prediction of central nervous system embryonal tumour outcome based on gene expression , 2002, Nature.

[17]  T. Braun,et al.  The Neuronal Basic Helix-Loop-Helix Transcription Factor NSCL-1 Is Dispensable for Normal Neuronal Development , 2002, Molecular and Cellular Biology.

[18]  M. Breslin,et al.  Neuroendocrine differentiation factor, IA-1, is a transcriptional repressor and contains a specific DNA-binding domain: identification of consensus IA-1 binding sequence. , 2002, Nucleic acids research.

[19]  V. Palma,et al.  Hedgehog–GLI signaling and the growth of the brain , 2002, Nature Reviews Neuroscience.

[20]  S. Pazzaglia,et al.  High incidence of medulloblastoma following X-ray-irradiation of newborn Ptc1 heterozygous mice , 2002, Oncogene.

[21]  Stephen B. Baylin,et al.  Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer , 2003, Nature.

[22]  Michael D. Cole,et al.  Nmyc upregulation by sonic hedgehog signaling promotes proliferation in developing cerebellar granule neuron precursors , 2003, Development.

[23]  J. Rutka,et al.  Transcriptional profiling of medulloblastoma in children. , 2003, Journal of neurosurgery.

[24]  J. Karlsson,et al.  The LIM-only protein LMO4 modulates the transcriptional activity of HEN1. , 2003, Biochemical and biophysical research communications.

[25]  M. Breslin,et al.  NeuroD1/E47 Regulates the E-box Element of a Novel Zinc Finger Transcription Factor, IA-1, in Developing Nervous System* , 2003, Journal of Biological Chemistry.

[26]  Robert J. Wechsler-Reya,et al.  Transcriptional profiling of the Sonic hedgehog response: A critical role for N-myc in proliferation of neuronal precursors , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[27]  C. Wetmore,et al.  Sonic hedgehog in normal and neoplastic proliferation: insight gained from human tumors and animal models. , 2003, Current opinion in genetics & development.

[28]  R. Gilbertson,et al.  Medulloblastoma: signalling a change in treatment. , 2004, The Lancet. Oncology.

[29]  T. MacDonald,et al.  Current treatment of medulloblastoma: recent advances and future challenges. , 2004, Seminars in oncology.

[30]  L. Di Marcotullio,et al.  REN(KCTD11) is a suppressor of Hedgehog signaling and is deleted in human medulloblastoma. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[31]  G. Stein,et al.  NeuroD: the predicted and the surprising. , 2004, Molecules and cells.

[32]  Isaac S Kohane,et al.  Conserved mechanisms across development and tumorigenesis revealed by a mouse development perspective of human cancers. , 2004, Genes & development.

[33]  L. Di Marcotullio,et al.  Hedgehog checkpoints in medulloblastoma: the chromosome 17p deletion paradigm. , 2005, Trends in molecular medicine.

[34]  R. F. Luco,et al.  IA1 is NGN3‐dependent and essential for differentiation of the endocrine pancreas , 2006, The EMBO journal.

[35]  C. Birchmeier,et al.  The zinc-finger factor Insm1 (IA-1) is essential for the development of pancreatic beta cells and intestinal endocrine cells. , 2006, Genes & development.

[36]  I. Screpanti,et al.  Alternative splicing of the ErbB-4 cytoplasmic domain and its regulation by hedgehog signaling identify distinct medulloblastoma subsets , 2006, Oncogene.

[37]  G. Fishell,et al.  Morphogen to mitogen: the multiple roles of hedgehog signalling in vertebrate neural development , 2006 .