The role of hedgehog-BMP4 signaling in the patterning of coelomic mesoderm and the onset of gonadogenesis

All organogenesis is triggered by various cellular behaviors, based on early embryonic patterning. At the onset of the formation of the ovary or testis, a subset of coelomic epithelial cells undergo (1) epithelial-to-mesenchymal transition (EMT) and subsequent ingression, (2) gonadal differentiation, (3) maintenance of stem-like state at outer layer, and (4) acquisition of the capability to retain primordial germ cells (PGCs), in early embryos. The specific embryonic patterning responsible for these cellular behaviors represents a long-standing question in developmental biology. We addressed this question using chicken embryo, a suitable model system for cell-labeling experiments and spatiotemporally restricted gene manipulation. We found that the ventral part of medial lateral plate mesoderm (M-LPM), a precursor of coelomic epithelium, initiates gonadogenesis by undergoing ingression. By contrast, dorsal M-LPM did not undergo ingression or form gonad. Sonic Hedgehog (SHH)-BMP4 signaling establishes this dorsoventral pattern in M-LPM and initiates gonadogenesis. SHH protein is secreted from the endoderm, which is located ventral to LPM, and reaches ventral but not dorsal M-LPM. As a result, Hedgehog (Hh) signaling triggers several cellular behaviors involved in initiation of gonadogenesis in ventral M-LPM. Downstream of Hh signaling, BMP4 dynamically changes its expression and functions. It is well known that BMP4 is expressed throughout the whole LPM and establishes the mediolateral axis in the early embryo. Thereafter, at the onset of gonadogenesis, its expression is restricted to the ventral part and thus forms a dorsoventral pattern in the M-LPM in a Hh-dependent manner. As a result, BMP4 causes multiple cellular behaviors involved in gonad formation in the ventral M-LPM. Furthermore, other recent studies imply that these cellular behaviors are regulated by several molecules, such as SNAIL2, NUMB, and SDF1, at the downstream of Hh-BMP4 signaling.