WNT/β-catenin modulates the axial identity of embryonic stem cell-derived human neural crest

• Published in: Development (Cambridge) Vol. 146; no. 16
• Main Authors: Gomez, Gustavo A, Prasad, Maneeshi S, Wong, Man, Charney, Rebekah M, Shelar, Patrick B, Sandhu, Nabjot, Hackland, James O S, Hernandez, Jacqueline C, Leung, Alan W, García-Castro, Martín I
• Format: Journal Article
• Language: English
• Published: England The Company of Biologists Ltd 29-08-2019
• Subjects: Human Development; Human embryonic stem cells; WNT dose/magnitude; HOX genes; Anterior-posterior axis; Neural crest
• ISSN: 0950-1991; 1477-9129
• DOI: 10.1242/dev.175604

WNT/β-catenin signaling is crucial for neural crest (NC) formation, yet the effects of the magnitude of the WNT signal remain ill-defined. Using a robust model of human NC formation based on human pluripotent stem cells (hPSCs), we expose that the WNT signal modulates the axial identity of NCs in a dose-dependent manner, with low WNT leading to anterior OTX
HOX
NC and high WNT leading to posterior OTX
HOX
NC. Differentiation tests of posterior NC confirm expected derivatives, including posterior-specific adrenal derivatives, and display partial capacity to generate anterior ectomesenchymal derivatives. Furthermore, unlike anterior NC, posterior NC exhibits a transient TBXT
/SOX2
neuromesodermal precursor-like intermediate. Finally, we analyze the contributions of other signaling pathways in posterior NC formation, which suggest a crucial role for FGF in survival/proliferation, and a requirement of BMP for NC maturation. As expected retinoic acid (RA) and FGF are able to modulate HOX expression in the posterior NC. Surprisingly, early RA supplementation prohibits NC formation. This work reveals for the first time that the amplitude of WNT signaling can modulate the axial identity of NC cells in humans.