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Autonomic neurocristopathy-associated mutations in PHOX2B dysregulate Sox10 expression
Mayumi Nagashimada, … , Teruhiko Wakayama, Hideki Enomoto
Mayumi Nagashimada, … , Teruhiko Wakayama, Hideki Enomoto
Published August 27, 2012
Citation Information: J Clin Invest. 2012;122(9):3145-3158. https://doi.org/10.1172/JCI63401.
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Research Article Article has an altmetric score of 2

Autonomic neurocristopathy-associated mutations in PHOX2B dysregulate Sox10 expression

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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

Mayumi Nagashimada, Hiroshi Ohta, Chong Li, Kazuki Nakao, Toshihiro Uesaka, Jean-François Brunet, Jeanne Amiel, Delphine Trochet, Teruhiko Wakayama, Hideki Enomoto

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Figure 3

Impaired migration and differentiation of enteric ganglion progenitors in NPARM PHOX2B embryos.

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Impaired migration and differentiation of enteric ganglion progenitors i...
(A–C) ISH analysis of Sox10 expression in ENCCs. Arrows indicate the foreguts of E10.5 embryos. Insets in the upper-right corners are larger magnifications of boxed areas. (D–F and H–J) Phox2b/Sox10 double immunostaining of E12 gut. Invasion of ENCCs in the hindgut mesenchyme (D) is retarded in NPARM PHOX2B embryos (E and F). ENCC density was noticeably lower in the mutant than in WT midgut. (G) Schematic representation showing the gut morphology at E12. Areas covered by ENCCs in WT hindgut are shown in green. (H–J) Larger magnification of the midgut regions. Arrows indicate neuronally committed cells expressing WT Phox2b, but not Sox10. (K–P) TuJ1 staining of embryonic gut. TuJ1+ cells are drastically decreased in NPARM PHOX2B embryos (L and M). Extinguishment of Sox10 expression in these early differentiating neurons is also impaired in NPARM PHOX2B embryos (arrows in O and P). Scale bars: 10 μm (P); 20 μm (J); 200 μm (C, F, and M).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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