RT Journal Article
SR Electronic
T1 The timing of signaling events in the BMP, WNT, and Nodal cascade determines self-organized fate patterning in human gastruloids
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 440164
DO 10.1101/440164
A1 Sapna Chhabra
A1 Lizhong Liu
A1 Ryan Goh
A1 Aryeh Warmflash
YR 2018
UL http://biorxiv.org/content/early/2018/10/10/440164.abstract
AB During gastrulation, the pluripotent epiblast is patterned into the three germ layers, which form the embryo proper. This patterning requires a signaling cascade involving the BMP, Wnt and Nodal pathways; however, how these pathways function in space and time to generate cell-fate patterns remains unknown. Using a human gastruloid model, we show that BMP signaling initiates a wave of Wnt signaling, which in turn, initiates a wave of Nodal signaling. While Wnt propagation depends on continuous BMP activity, Nodal propagates independently of upstream signals. Wnt and Nodal synergistically induce mesendoderm, and, surprisingly, the region of differentiation is distinguished by particular relative timing of signaling events, not particular activity levels. Using mathematical modeling, we show the observed signaling dynamics are incompatible with WNT and NODAL functioning as Turing systems. Thus, signaling timing, in the absence of a stable spatial gradient in signaling activity has the potential to mediate epiblast patterning.