Bicaudal C functions as a post-transcriptional bistable switch in left–right axis specification

• Applicant: Professor Dr. Axel Schweickert
• Subject Area: Developmental Biology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 573477578

Bistability, i.e., switching between two stable states in response to external stimuli, is a recurring principle in developmental biology. It plays a central role in cell fate determination, embryonic patterning, and cell cycle regulation. On a molecular level, bistability is often based on effector–inhibitor interactions operating through positive and negative feedback loops. One example is the establishment of the left–right (LR) body axis in vertebrates. In the so-called LR organizer (LRO) of the neurula-stage embryo, motile monocilia generate a leftward fluid flow – the first detectable LR asymmetry. This flow is sensed by sensory LRO cells (sLRO), which bear immotile cilia and express both the TGFß morphogen Nodal and its Cerberus-type inhibitor Dand5. Prior to flow onset, these two molecules exist in a stable equilibrium. Upon detection of leftward flow, dand5 mRNA translation is post-transcriptionally inhibited and the mRNA is degraded in left-sided sLRO cells. As a result, Nodal is derepressed and its expression rapidly spreads via a positive feedback loop. Ultimately, the left-sided determinant, the transcription factor Pitx2, is induced. The induction of this left-sided Nodal cascade represents the second stable state of the bistable system. Our recent work in Xenopus embryos shows that the RNA-binding protein Bicaudal-C (Bicc1) regulates both the Nodal/Dand5 equilibrium and the flow-induced repression of dand5. Thus, Bicc1 acts as a molecular switch of bistability during symmetry breaking. The aim of the present proposal is to elucidate the molecular mechanisms underlying this switching function. We hypothesize that two known interaction partners of Bicc1, the proteins Anks3 and Anks6, play key roles in modulating its function in sLRO cells. Initial data show that both loss of function (LOF) and gain of function (GOF) of anks3 or anks6 disrupt LR development in Xenopus. This project addresses three tightly interlinked questions: First, we will use a systematic LOF/GOF approach to define the roles of Anks3 and Anks6 in LR development in detail. Second, we will investigate how these proteins influence Bicc1 and potentially modulate its switching function. Third, we will explore the contribution of Bicc1-dependent RNA condensates to the regulation of dand5. Since Bicc1, Anks3, and Anks6 are capable of forming or regulating RNA granules via liquid–liquid phase separation (LLPS) – similar to stress granules or processing bodies – these structures may provide the molecular basis for the post-transcriptional control of dand5. We propose that such granules play a central role in establishing bistability and defining the LR axis.

• DFG Programme: Research Grants