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 pfkfb4 (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 in vivo. We find that PFKFB4 is essential both for specification of functional premigratory NC and for its migration. PFKFB4-depleted embryos fail to activate n-cadherin 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.
Footnotes
Competing interests
The authors declare no competing or financial interests.
Author contributions
Conceptualization: A.L.F., C.P., A.H.M.-B.; Methodology: A.L.F., F.M., C.B., P.P., C.P., A.H.M.-B.; Validation: A.L.F., F.M., C.P., A.H.M.-B.; Investigation: A.L.F., F.M., C.B., P.P., M.S., C.P., A.H.M.-B.; Resources: F.M.; Data curation: A.L.F.; Writing - original draft: A.L.F., F.M., C.B., P.P., A.H.M.-B.; Writing - review & editing: A.L.F., F.M., C.B., P.P., M.S., A.H.M.-B.; Visualization: A.L.F., F.M., C.B., P.P., A.H.M.-B.; Supervision: A.H.M.-B.; Project administration: A.H.M.-B.; Funding acquisition: A.H.M.-B.
Funding
This study was supported by funding from Université Paris-Sud, Centre National de la Recherche Scientifique, Association pour la Recherche sur le Cancer (ARC PJA20131200185), Agence Nationale de la Recherche (ANR Programmes Blanc CrestNet and CrestNetMetabo) (ANR-Blanc- SVSE2-2011- CRESTNET and ANR-15-CE13-0012-01-CRESTNETMETABO), Fondation pour la Recherche Médicale (FRM; Programme Equipes Labellisées DEQ20150331733) and Institut Universitaire de France (to A.H.M.-B). A.L.F. was a PhD fellow of the French Ministry for Research and Education (MENRT) and Fondation pour la Recherche Médicale (FDT20140930900). M.S. was a PhD fellow funded by Fondation pour la Recherche Médicale (ECO20160736105).
Supplementary information
Supplementary information available online at http://dev.biologists.org/lookup/doi/10.1242/dev.157644.supplemental
- Received July 25, 2017.
- Accepted October 7, 2017.
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