A molecular mechanism of symmetry breaking in the early chick embryo

Abstract

The first obvious sign of bilateral symmetry in mammalian and avian embryos is the appearance of the primitive streak in the future posterior region of a radially symmetric disc. The primitive streak marks the midline of the future embryo. The mechanisms responsible for positioning the primitive streak remain largely unknown. Here we combine experimental embryology and mathematical modelling to analyse the role of the TGFβ-related molecules BMP4 and Vg1/GDF1 in positioning the primitive streak. Bmp4 and Vg1 are first expressed throughout the embryo, and then become localised to the future anterior and posterior regions of the embryo, where they will, respectively, inhibit or induce formation of the primitive streak. We propose a model based on paracrine signalling to account for the separation of the two domains starting from a homogeneous array of cells, and thus for the topological transformation of a radially symmetric disc to a bilaterally symmetric embryo.

Figure 1

BMP4 and Vg1 dynamics in the early embryo. (A–E) Graft of BMP4-bead in the posterior marginal zone (A) inhibits Vg1 expression (B) and axis formation as indicated by Brachyury (Bra) expression (D) (C, E: controls). (F–H) Anterior BMP4-bead (F) induces Vg1 expression (G, arrow, H, control). (I–K) Multiple BMP4-conjugated bead graft (I) induces multiple axes (Bra expression) (J, arrows) (K, control). (L–N) Vg1 misexpression anteriorly (L) causes Bmp4 downregulation (M), (N, control). Red circle: BMP4 bead in all figures except (M,N), where it indicates the pellet of COS cells. Posterior (p) to the bottom. Scale bar: 1 mm.

Figure 2

Numerical simulations of the model describing Bmp4 and Vg1 dynamics. (A) In agreement with experimental results, two opposite gradients of Bmp4 and Vg1 form in the embryo starting from a homogeneous initial situation. The images correspond to numerical simulations starting with three different initial conditions. (B) Ectopic expression of BMP4 posteriorly inhibits Vg1. (C) In contrast, ectopic BMP4 anteriorly induces local Vg1. (D) Vg1 anteriorly induces its own expression and inhibits Bmp4. Blue and red indicate lower and higher levels of expression, respectively. The values of parameters used in these simulations are shown in SM2.

Figure 3

Gata2 is a potential candidate for factor F_B. (A) Initial and final distribution of Gata2 as predicted by the model. Left: Gata2 is initially homogeneously distributed. Right: After model simulation, Gata2 appears segregated to the anterior region. (B) Numerical simulations of Gata2 knockdown produce a local Bmp4 downregulation. (C–E) Numerical simulation of ectopic BMP4 anteriorly results in local Gata2 upregulation (C), confirming the experimental result (D, arrow) (E, control). Posterior (p) to the bottom. Red circle: BMP4 (D) or control (E) bead. Scale bar: 1 mm.