Abstract
Hirschsprung Disease (HSCR) and/or hypoganglionosis are common pediatric disorders that arise from developmental deficiencies of enteric neural crest cells (ENCCs). Retinoid acid (RA) signaling has been shown to affect neural crest (NC) development. However, the mechanisms underlying RA deficiency-induced HSCR or hypoganglionosis are not well-defined. In this report, we found that in HSCR patient bowels, the RA nuclear receptor RARα and its interacting coregulator CREB-binding protein (CBP) were expressed in enteric neural plexuses in the normal ganglionic segment. However, the expression of these two genes was significantly inhibited in the pathological aganglionic segment. In a Xenopus laevis animal model, endogenous RARα interacted with CBP and was expressed in NC territory. Morpholino-mediated knockdown of RARα blocked expression of the NC marker genes Sox10 and FoxD3 and inhibited NC induction. The morphant embryos exhibited reduced nervous cells in the gastrointestinal anlage, a typical enteric nervous deficiency-associated phenotype. Injection of CBP mRNA rescued NC induction and reduced enteric nervous deficiency-associated phenotypes. Our work demonstrates that RARα regulates Sox10 expression via CBP during NC induction, and alteration of the RA-CBP signaling pathway may contribute to the development of enteric nervous system disorders.
Highlights
Hirschsprung disease (HSCR) and/or hypoganglionosis are common congenital disorders of the enteric nervous system [1]
We found that RARα regulates Sox10 expression via CREB-binding protein (CBP) during neural crest (NC) induction, and alteration of the Retinoid acid (RA)-CBP signaling pathway may contribute to the development enteric nervous system disorders
To explore roles of RARα and CBP in enteric nervous system development, we first investigated the enteric expression patterns in excision bowels from 9 cases Hirschsprung Disease (HSCR) in children
Summary
Hirschsprung disease (HSCR) and/or hypoganglionosis are common congenital disorders of the enteric nervous system [1]. The predominant feature of HSCR is a lack of enteric neurons in the end of the bowel; whereas hypoganglionosis refers to reduced enteric neurons throughout the entire bowel [1]. Both conditions are due to developmental abnormities of the neural crest (NC) [2]. The neural crest (NC) is a group of transient pluripotent cells induced by complex morphogen signals at the neural-epidermis border [3] Border region genes such as Pax, Zic, Msx, and Sox synergistically activate downstream specifier genes and accomplish NC induction [3,4,5]. After induction, which is usually marked by FoxD3 or Slug expression, NC cells migrate out from the dorsal neural tube to different destinations where they develop into various tissues and organs such as pigment cells, cranial facial cartilage, heart outflow tract, and the enteric nervous system [5, 6]
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