Mechanisms of Wnt signaling in early vertebrate development

Mechanisms of Wnt signaling in early vertebrate development

Wnt/beta-catenin signalling plays an important role in early development and we are interested in studying mechanism of pathway regulation in particular in the context of early embryonic patterning. Wnt/beta-catenin signalling is now a vast field and we are focusing on the molecular events occuring at the plasma membrane, where we study the Wnt receptor LRP6 (LDL receptor-related protein 6).

We also showed that in Xenopus embryogenesis, Wnt/beta-catenin signaling plays an important role in antero-posterior patterning of the early central nervous system. Our results demonstrated a posteriorizing gradient of Wnt signalling, which regulates dose-dependently positional information from the forebrain to spinal cord. Importantly, we revealed an endogenous antero-posterior gradient of Wnt/beta-catenin signalling in the presumptive neural plate of the Xenopus gastrula. Together with other data this led to the proposal of perpendicular activity gradients of Wnt and BMPs, which regulate early CNS patterning (Fig. 1).

Fig. 1 Double-gradient model for A-P and D-V axial patterning
© dkfz.de

The model shows how perpendicular activity gradients of Wnts and bone morphogenetic proteins (BMPs) regulate head-to-tail (A-P) and dorsal-ventral (D-V) CNS patterning. The colour scales of the arrows indicate the signalling gradients; arrows indicate the spreading of the signals. Patterning begins at gastrula stages, but for clarity, it is depicted in an early amphibian neurula. The formation of head, trunk and tail requires increasing Wnt activity. Anterior and posterior are to the left and right, respectively.

Fig. 2: Dickkopf1mutant embryos are headless. Day 17 mouse embryos wild type (left) and dkk1 null mutant (right).
© dkfz.de

We previously identified an important regulator of Spemann's organizer, dickkopf1(dkk1), member of a new family of secreted Wnt antagonists, which inhibit Lrp6. Dkk1 functions in embryonic head development in mouse (Fig. 2). While the gene was initially characterized as a developmental regulator, dkk1 is gaining increasingly medical attention, since it has been implicated in bone physiology and myeloma by others. We currently study the role of LRP6 during Xenopus and mouse development, including CNS. Towards this end we identify interacting proteins of these proteins and elucidate their role in Wnt signalling and early development. This led to the recent discovery of Rspondins and Casein kinase 1 gamma as novel Wnt regulators, which are also involved in CNS patterning.

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