Perturbation of Hoxb5 signaling in vagal and trunk neural crest cells causes apoptosis and neurocristopathies in mice

Abstract

Neural crest cells (NCCs) migrate from different regions along the anterior-posterior axis of the neural tube (NT) to form different structures. Defective NCC development causes congenital neurocristopathies affecting multiple NCC-derived tissues in human. Perturbed Hoxb5 signaling in vagal NCC causes enteric nervous system (ENS) defects. This study aims to further investigate if perturbed Hoxb5 signaling in trunk NCC contributes to defects of other NCC-derived tissues besides the ENS. We perturbed Hoxb5 signaling in NCC from the entire NT, and investigated its impact in the development of tissues derived from these cells in mice. Perturbation of Hoxb5 signaling in these NCC resulted in Sox9 downregulation, NCC apoptosis, hypoplastic sympathetic and dorsal root ganglia, hypopigmentation and ENS defects. Mutant mice with NCC-specific Sox9 deletion also displayed some of these phenotypes. In vitro and in vivo assays indicated that the Sox9 promoter was bound and trans-activated by Hoxb5. In ovo studies further revealed that Sox9 alleviated apoptosis induced by perturbed Hoxb5 signaling, and Hoxb5 induced ectopic Sox9 expression in chick NT. This study demonstrates that Hoxb5 regulates Sox9 expression in NCC and disruption of this signaling causes Sox9 downregulation, NCC apoptosis and multiple NCC-developmental defects. Phenotypes such as ENS deficiency, hypopigmentation and some of the neurological defects are reported in patients with Hirschsprung disease (HSCR). Whether dysregulation of Hoxb5 signaling and early depletion of NCC contribute to ENS defect and other neurocristopathies in HSCR patients deserves further investigation.

Chicken trunk neural crest migration visualized with HNK1

“…Because they are the main providers of all trunk sensory ganglia and Schwann cells, their correct migratory patterns have been heavily studied through functional approaches. The most commonly used is the genetic approach in mouse and zebrafish (Kam et al, 2014; Pryor et al, 2014; Vermillion et al, 2014). However, chicken is the most and best studied model organism given it easiness and hardiness to manipulate.…”

Suppressive action of miRNAs to ARP2/3 complex reduces cell migration and proliferation via RAC isoforms in Hirschsprung disease

“…During this process, the alteration of internal environment and aberrant expression of genes or molecules may contribute to aganglionosis . In general, the pathogenesis of HSCR concerns with the aberrant function of ENCCs . Many factors affect the function of ENCCs, such as changes of internal environment, aberrant expression of various cell components, nutritional status, abnormal activation of cell signalling and exogenous chemical exposure.…”

Long none coding RNA HOTTIP/HOXA13 act as synergistic role by decreasing cell migration and proliferation in Hirschsprung disease

“…What is more, perturbation of HOXB5 signaling in NCC from the entire neural tube causes apoptosis and neurocristopathies in mice [30]. Besides, HOXA9 and HOXA13 are considered as early and organised pattern of ENS development in the zebrafish model.…”