title: Autonomic neurocristopathy-associated mutations in PHOX2B dysregulate Sox10 expression.
abstract: The most common forms of neurocristopathy in the autonomic nervous system are Hirschsprung disease (HSCR), resulting in congenital loss of enteric ganglia, and neuroblastoma (NB), childhood tumors originating from the sympathetic ganglia and adrenal medulla. The risk for these diseases dramatically increases in patients with congenital central hypoventilation syndrome (CCHS) harboring a nonpolyalanine repeat expansion mutation of the Paired-like homeobox 2b (PHOX2B) gene, but the molecular mechanism of pathogenesis remains unknown. We found that introducing nonpolyalanine repeat expansion mutation of the PHOX2B into the mouse Phox2b locus recapitulates the clinical features of the CCHS associated with HSCR and NB. In mutant embryos, enteric and sympathetic ganglion progenitors showed sustained sex-determining region Y (SRY) box10 (Sox10) expression, with impaired proliferation and biased differentiation toward the glial lineage. Nonpolyalanine repeat expansion mutation of PHOX2B reduced transactivation of wild-type PHOX2B on its known target, dopamine β-hydroxylase (DBH), in a dominant-negative fashion. Moreover, the introduced mutation converted the transcriptional effect of PHOX2B on a Sox10 enhancer from repression to transactivation. Collectively, these data reveal that nonpolyalanine repeat expansion mutation of PHOX2B is both a dominant-negative and gain-of-function mutation. Our results also demonstrate that Sox10 regulation by PHOX2B is pivotal for the development and pathogenesis of the autonomic ganglia.
authors.affiliation: Laboratory for Neuronal Differentiation and Regeneration, RIKEN Center for Developmental Biology, Kobe, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Nagashimada
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ohta
authors.forename: Chong
authors.initials: C
authors.lastname: Li
authors.forename: Kazuki
authors.initials: K
authors.lastname: Nakao
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Uesaka
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Brunet
authors.forename: Jeanne
authors.initials: J
authors.lastname: Amiel
authors.forename: Delphine
authors.initials: D
authors.lastname: Trochet
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Wakayama
authors.forename: Hideki
authors.initials: H
authors.lastname: Enomoto
mesh_terms: D000818:Animals; D002452:Cell Count; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D004742:Enhancer Elements, Genetic; D017615:Enteric Nervous System / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D005728:Ganglia, Sympathetic / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D041981:Gastrointestinal Tract / Q000196:embryology / Q000294:innervation / Q000473:pathology; D005786:Gene Expression Regulation; D055879:Gene Knock-In Techniques; D006627:Hirschsprung Disease / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D007040:Hypoventilation / Q000151:congenital / Q000235:genetics; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D009432:Neural Crest / Q000378:metabolism / Q000473:pathology; D058953:Neural Stem Cells / Q000502:physiology; D009447:Neuroblastoma / Q000235:genetics; D009457:Neuroglia / Q000502:physiology; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D010455:Peptides / Q000235:genetics; D010641:Phenotype; D020449:Repetitive Sequences, Amino Acid / Q000235:genetics; D055757:SOXE Transcription Factors / Q000235:genetics* / Q000378:metabolism; D017384:Sequence Deletion; D020182:Sleep Apnea, Central / Q000235:genetics; D018874:Spheroids, Cellular / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D015533:Transcriptional Activation
chemical_list: D018398:Homeodomain Proteins; C109220:NBPhox protein; D010455:Peptides; D055757:SOXE Transcription Factors; C527924:Sox10 protein, mouse; D014157:Transcription Factors; C019529:polyalanine