Regulatory Functions of Capicua in Human Mast Cells: Cell Cycle Progression, Lineage Identity, and Transcriptional Programs

• Applicant: Dr. Magda Babina
• Subject Area: Dermatology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 579992068

Capicua (CIC) was initially discovered as a key player in embryonic development and normal cell fate determination, later identified as a tumor suppressor that constitutively represses receptor tyrosine kinase (RTK)-responsive genes. Moreover, CIC is critically involved in immune regulation, and neuronal function. Mast cells (MCs) exhibit characteristics of both systems: They serve as important sentinel cells of the innate immune system to combat infections, while also forming functional units with neurons, with which they even share several attributes. Packed with large amounts of potent mediators, MCs can trigger allergic symptoms and contribute to various inflammatory disorders when not properly constrained. A primary MC-driven disease in which proliferation becomes uncontrolled is mastocytosis, with its most aggressive form being MC leukemia, which presents significant therapeutic challenges. Our preliminary research has shown that CIC is highly expressed in skin MCs and undergoes extensive phosphorylation upon activation of the cells’ major RTK, KIT. This phosphorylation results in CIC translocation and degradation, processes regulated by ERK action to inactivate the repressor. In fact, many effects of the Ras/MEK/ERK cascade are now recognized to occur through the inhibition of CIC. However, CIC is not only influenced by KIT activation, but it also affects KIT activity in return. Indeed, CIC can repress KIT signaling and functional outputs, with its levels negatively correlating with SCF sensitivity. Intriguingly, the elimination of CIC alone can trigger MC hyperplasia in vivo, indicating that CIC is critical for maintaining MC frequency at bay. Building on our extensive preliminary dataset, this proposal aims to delve deeper into CIC's role in MC biology. We will explore its dynamic regulation by other nuclear components, investigate its role in maintaining MC integrity and maturation, and examine CIC’s function as a suppressor of (excessive) proliferation. We will identify CIC's genome-wide binding sites in dermal MCs and analyze changes in the transcriptional landscape following its silencing. Given that MCs in their native skin environment are among the highest expressers of CIC body-wide, while its abundance decreases when cells transform malignantly, this project will eventually test the hypothesis that defects in the CIC network predispose to MC proliferative disorders. Together, our project will provide a thorough understanding of whether and how CIC contributes to MC identity and characterize the molecular underpinnings of its network in MCs of different proliferation rates, such as quiescent skin MCs, actively-cycling counterparts, MCs with an activating KIT mutation, and cancerous MCs. These issues are of fundamental interest and clinical relevance alike, with the potential for CIC stabilization to become an option to interfere with hyperproliferation of the lineage.

• DFG Programme: Research Grants