Bone Morphogenetic Proteins during dorsoventral patterning and gastrulation movements

The future fate of a cell in the later animal is determined by the position of its precursor cells at late blastula stages. Of particular importance is the position along the future dorsoventral axis. Based on ventralized or dorsalized mutants, we could show that the signaling proteins Bmp2b and Bmp7, their type I receptor Alk8, and the Bmp-regulated transcription factor Smad5 are required for ventral cell fate specification, whereas dorsal development occurs when Bmp signaling is blocked by the secreted Bmp inhibitor Chordin. Currently, we are analyzing several other proposed modulators of Bmp signaling (e.g. Crossveinless 2), using morpholino antisense technology for loss-of-function studies, but also various biochemical techniques to unravel the molecular mechanisms of protein action.

In addition, we study several other roles of Bmp signaling during early development. For instance, we have indication that Bmp signaling is required for early cell survival. In addition, early Bmp signaling has some kind of embryonic stem cell maintaining-effect, generally blocking cell specification / differentiation steps. In the ectoderm, this effect is mediated by transcriptional activation of ∆Np63, encoding a transcription factor related to and antagonizing the tumor suppressor p53. Gain- and loss-of-function studies showed that ∆Np63 acts downstream of Bmp signaling to block neural development in ventral regions of the ectoderm, thereby leaving it available for epidermal specification, which occurs much later. Furthermore, Bmp signaling has a chemotactic effect, determining the direction of cell migrations in the lateral mesoderm during dorsal convergence, one of the morphogenetic movements of gastrulation. This cell-guiding function of the Bmp gradient is achieved by establishing a reverse gradient of Cadherin-dependent cell-cell adhesiveness. Bmp signalling is known to regulate downstream components on the transcriptional and post-translational level. However, the exact transcriptional target genes and / or target proteins of Bmp signalling mediating the in vivo effects during early development are largely unknown. Differential hybridization assays and differential proteomics approaches are in progress to identify them. Identified genes and proteins will be further analyzed, employing gain- and loss-of- function studies.