Mirka Uhlirova

Institute for Genetics

Prof. Dr. Mirka Uhlirova CECAD Cologne
Prof. Dr. Mirka Uhlirova

Principal Investigator 

Research Areas

Signaling and Gene Expression

To maintain cell and tissue function and homeostasis in multicellular organisms, cells need to constantly respond to different signals and adapt their behaviors. This is achieved through precise regulation of signaling pathways that govern gene expression.

Research Focus

The Uhlirova Lab explores the pleiotropic functions of stress-inducible signaling pathways and the downstream mechanisms orchestrating gene expression. We investigate how diverse stress signals modulate transcription factor and spliceosome activities during development and physiology. Additionally, we examine how dysfunction in transcription and splicing machinery impacts cell and tissue behaviors, as well as organismal homeostasis during aging and disease. Our approach integrates functional genetics in Drosophila and mouse models with a diverse array of techniques, including molecular and cell biology, biochemistry, multi-omic approaches, and advanced microscopy.

The ability of cells to sense and interpret various stress signals, generating meaningful biological responses by coordinating transcription and pre-mRNA splicing is critical for the development, maintenance, and healthspan of multicellular organisms.

Our Goals

Transcription and pre-mRNA splicing are essential steps in the regulation of gene expression in multicellular organisms. Their close interplay enables the generation of specific gene expression patterns required for the differentiation of functionally diverse cell types, but also allows the fine-tuning of their responses to various cues, providing a dynamic and adaptive ability to navigate their ever-changing environment.

Our goal is to understand how co-transcriptional splicing governs essential cellular behaviors, such as growth, proliferation, cell death, and cell migration both in physiological conditions and under stress. We particularly focus on epithelia and immune cells and their interactions. We investigate the link between pre-mRNA splicing and the maintenance of transcriptome and genome integrity.

  • We explore the mechanisms that control the assembly and functional plasticity of the spliceosome.
  • Additionally, we investigate the cascade of cellular and molecular events triggered by transcription factor and spliceosome dysfunction and investigating the nature of stress signaling responses and their impact on the loss of cell, tissue, and organismal homeostasis.

In summary, our research aims to unravel the intricate connections between transcription, pre-mRNA splicing, and their collective impact on cellular behavior, tissue homeostasis, aging, and disease development. By elucidating these processes, we seek to provide valuable insights into the function of fundamental biological machines, with potential implications for therapeutic intervention.

We demonstrated the pivotal role of spliceosome biogenesis in the development, tissue maintenance, and overall healthspan of multicellular organisms (Erkelenz et al., 2021, NAR) and identified C/EBP transcription factors as key drivers of a stress response program and senescent-like state triggered by spliceosome dysfunction (Stankovic et al., 2024, NAR).

We established the Drosophila model to study the mechanisms underlying an autosomal dominant form of an eye-blinding degenerative disease retinitis pigmentosa caused by mutations in a core splicing factor Prp8 (Stankovic et al., 2020, DMM).

We defined a physiological role for the transcription factor Ets21c, the fly ortholog of mammalian proto-oncogenes ERG and FLI-1, in the regulation of the regenerative program in the Drosophila adult intestine and highlighted its role in the trade-off mechanisms between stress resilience and longevity (Mundorf et al., 2019, Cell Rep.).

Our research has provided novel insights into how tumor cells exploit mechanosensitive cellular machinery to promote malignancy (Külshammer et al., 2022, FEBS J).

Finally, our interest in the mechanisms of inter-organ communication identified the interaction between a phagocytic receptor Eater and an extracellular matrix component Multiplexin, the fly ortholog of human Collagen XV/XVIII, to be necessary and sufficient for blood cell homing and their interactions with hematopoietic microenvironments (Csordas et al., 2020, Elife). 

Key Publications

  1. ​​​​​​​​​​​​​​Stankovic, D., Tain, SL., Uhlirova, M. (2024). Xrp1 governs the stress response program to spliceosome dysfunction. Nucleic Acids Research. gkae055, doi: 10.1093/nar/gkae055
  2. Külshammer, E., Kilinc, M., Csordás, G., Bresser, T., Nolte, H., Uhlirova, M. (2022). The mechanosensor Filamin A/Cheerio promotes tumourigenesis via specific interactions with components of the cell cortex. FEBS J. 289: 4497-4517. doi: 10.1111/febs.16408.
  3. Erkelenz, S., Stankovic, D., Mundorf, J., Bresser, T., Claudius, A-K., Boehm, V., Gehring, N.H., Uhlirova, M. (2021). Ecd promotes U5 snRNP maturation and Prp8 stability. Nucleic Acids Research 49, 1688-1707. doi: 10.1093/nar/gkaa1274
  4. Csordás, G., Grawe, F., Uhlirova, M. (2020). Eater cooperates with Multiplexin to drive the formation of hematopoietic compartments. Elife 9: e5729. doi: 10.7554/eLife.57297.
  5. Mundorf, J., Donohoe, C.D., McClure, C.D., Southall, T.D., Uhlirova, M. (2019). Ets21c governs tissue renewal, stress tolerance, and aging in the Drosophila intestine. Cell Reports 27, 3019-3033.e5. doi: 10.1016/j.celrep.2019.05.025.
Prof. Dr. Mirka Uhlirova CECAD Cologne
Prof. Dr. Mirka Uhlirova

Principal Investigator 

Research Areas