PFKFB4 control of Akt signaling is essential for premigratory and migratory neural crest formation

Abstract

Neural crest (NC) specification comprises an early phase, initiating immature NC progenitors formation at neural plate stage, and a later phase at neural fold stage, resulting in a functional premigratory NC that is able to delaminate and migrate. We found that the NC gene regulatory network triggers upregulation of (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4) during this late specification phase. As shown in previous studies, PFKFB4 controls AKT signaling in gastrulas and glycolysis rate in adult cells. Here, we focus on PFKFB4 function in NC during and after neurulation, using time-controlled or hypomorph depletions We find that PFKFB4 is essential both for specification of functional premigratory NC and for its migration. PFKFB4-depleted embryos fail to activate and late NC specifiers, and exhibit severe migration defects resulting in craniofacial defects. AKT signaling mediates PFKFB4 function in NC late specification, whereas both AKT signaling and glycolysis regulate migration. These findings highlight novel and essential roles of PFKFB4 activity in later stages of NC development that are wired into the NC gene regulatory network.

Kat2a and Kat2b Acetyltransferase Activity Regulates Craniofacial Cartilage and Bone Differentiation in Zebrafish and Mice

“…Gli1 is a transcription factor that is required for differentiation of neural crest cells [89,90], and the acetylation of Gli1 by Kat2b may be one of the potential contributors to the kat2b −/− cartilage phenotype. Another substrate of Kat2b, Akt1, has been found to be correlated to the regulation of neural crest cells specification and migration [91] and embryonic skeletal development [92], and mutated in patients with craniofacial defects, including mandible and frontal bone deformities [93]. In addition, acetylation of Akt1 by Kat2b has been shown to regulate cell proliferation and survival in vitro [61,94,95].…”

Cut loose and run: The complex role of ADAM proteases during neural crest cell development

“…Other studies have shown the importance of AKT phosphorylation and CNC migration (Bahm et al, 2017; Figueiredo et al, 2017). In particular, the Mayor group revealed that PDGFR stimulation results in increased AKT phosphorylation and N-cadherin expression, which in turn contributes to the transition from pre- to post-migratory CNC (Bahm et al, 2017).…”

Modeling Bainbridge-Ropers Syndrome in Xenopus laevis Embryos

“…The neural crest also seems atypical as seen by abnormal melanocyte patterning along the body axis and malformation of the dorsal fin (Figure 5A). In tailbud stage embryos, there is a strong reduction of twist marker expression ( Figure 5B), which is specific for head/craniofacial neural crest cells (Figueiredo et al, 2017). Additionally, neural crest derived head cartilage formation is perturbed and reduced in ASXL3 morphant embryos (Figure 5C).…”

“…Ovulation, in vitro fertilization, culture, explant dissection and treatment were as described (Re'em-Kalma et al, 1995;Bonstein et al, 1998). Embryos were stained with Alcian Blue for cartilage detection at tadpole stages (Figueiredo et al, 2017).…”

“…Whole-mount in situ hybridization was performed (Harland, 1991) with digoxigenin-labeled probes neural-specific tubulin (ntub), krox20, cdx4, twist (Gutkovich et al, 2010;Fonar et al, 2011;Figueiredo et al, 2017), and asxl3. Two Xenopus asxl3 probes were used.…”