Supervisor: Prof. Dr. Elmar Wahle


Specific aim(s)/topic(s) 

(1) The role of PARN in histone mRNA metabolism

(2) The role of PARN in cell stress

(3) Non-biased and comprehensive identification of PARN substrates


Background and significance

RNA is subject to many processing and decay reactions involving 3' exonucleases. Both in processing and decay, exonucleases are influenced by the 3'-end addition of non-encoded nucleotides to their substrates. For example, long poly(A) tails are added to mRNA by the 'canonical' poly(A) polymerase, and their gradual removal by poly(A)-specific 3' exonucleases is the first and often rate-limiting step in mRNA decay. As subsequent steps of mRNA decay are delayed until deadenylation is more or less complete, mRNA poly(A) tails are stabilizing modifications. More recently, the end-addition of just a few A and sometimes U residues has been discovered. All kinds of RNA molecules can be substrates for this type of reaction, the responsible enzymes are 'non-canonical' poly(A)/poly(U) polymerases, and oligoadenylation/uridylation promotes either rapid decay of the modified RNA or its processing by a 3' exonuclease; in this sense, oligoadenylation/uridylation is a destabilizing modification. Three types of conserved poly(A)-specific 3' exonuclease complexes have been relatively well studied: The CCR4-NOT complex carries the major activity for mRNA deadenylation in all organisms analyzed. The PAN complex plays a similar but supporting role. The role of the homodimeric poly(A)-specific ribonuclease (PARN) is less well understood. Its preference for poly(A) and a modest stimulation by a 5' cap on the substrate suggest mRNAs as substrates. However, several studies have not found a role in general mRNA decay. Functions in the degradation of a few specific mRNAs and under certain stress conditions have been suggested.

Supervisor: Prof. Dr. Christian Eckmann


Specific aim(s)/topic(s) 

(1) The role of GLD-4 in promoting germline stem cell self-renewal

(2) The role of GLD-4 and GLD-2 in promoting meiotic commitment


Background and significance

Our broad goal is to understand animal tissue development and pathology at the level of cytoplasmic gene expression regulation. We are particularly interested in the function of non-canonical poly(A) polymerases that modify mRNA molecules at their 3’ends and thereby control biological processes as diverse as cellular senescence, stress response, and gametogenesis.

Cytoplasmic poly(A) polymerases (cytoPAPs) are crucial regulators of post-transcriptional mRNA control and evolutionary conserved across metazoans. In contrast to canonical PAP, which generally localizes to the nucleus and associates with mRNA targets via an intrinsic RRM-type fold, cytoPAPs lack a similar region of conservation and possess no predictable RNA-binding domains. While canonical PAP polyadenylates mRNA precursors, cytoPAPs are proposed to be more specific in targeting mature RNAs. Together this suggests the existence of RNA-adaptor proteins that specifically recruit cytoPAPs to their target mRNAs; however, few RNA-adaptors and target mRNAs are known to date. Moreover, whereas canonical PAP is a very active enzyme in vitro, cytoPAPs are by themself very inefficient enzymes that display increased polyadenylation activity in the presence of additional protein cofactors, suggesting that cytoPAPs themselves might be highly regulated enzymes and part of larger ribonucleoprotein particles (mRNPs) controlling mRNA fates. Importantly, germ cell development relies heavily on cytoPAP function and its absence leads to sterility. The pleiotropy of the germ cell defects suggests that cytoPAPs promote the efficient translation of mRNAs that encode cell fate establishment and maintenance factors.

Supervisor: Prof. Dr. Mechthild Hatzfeld


Specific aim(s)/topic(s) 

(1) Post-transcriptional control of PKP1 expression via miRNAs and RNA-binding proteins (RBPs)

(2) Regulation of alternative PKP1 3’UTR processing


Background and significance

Plakophilin 1 (PKP1) was discovered as a component of the desmosomal plaque. It is a major constituent of desmosomes in the skin where it strengthens intercellular cohesion. However, PKP1 as well as the related plakophilins 2 (PKP2) and 3 (PKP3) are, in addition, detected in the cytoplasm and the nucleus. Their function in these compartments is still not well understood despite some recent progress in this field. PKP1 and 3 were found in stress granules, particles that are enriched in mRNAs, translation initiation factors and RNA-binding proteins (RBPs), and stimulate mRNA translation as well as cell proliferation in non-stressed cells. Typically, intercellular cohesion correlates with contact-dependent growth inhibition, and in agreement a downregulation of desmosomal proteins including plakophilins was detected in some tumor samples. However, an upregulation of PKP1 and 3 has also been described, which led to the suggestion that the contribution of desmosomes to carcinogenesis is context-dependent although this ‘context’ has not been revealed yet.

Supervisors: Prof. Dr. Guido Posern


Specific aim(s)/topic(s)

(1) The regulation of MRTF-A and its target genes by microRNAs

(2) Understanding the miRNA-MRTF circuitry in muscle cell differentiation 


Background and significance

The development and differentiation of muscle cells is a tightly regulated process including several signaling pathways, transcription factors and post-transcriptional processes. However, the details of the circuitries which govern the differentiation into a specific muscle subtype are not well understood, despite their significance in e.g. artheriosclerotic lesion formation and muscle regeneration.

The myocardin family of transcription factors plays an essential role for differentiation and function of both, skeletal and smooth muscle cells. They are coactivators of the Serum Response Factor (SRF) and control several muscle-specific genes, including skeletal muscle alpha-actin (acta1; SMA), smooth muscle alpha-actin (acta2; SkMA), myosin heavy chain and SM22. Whereas Myocardin expression is specific to smooth and cardiac muscle, the Myocardin-related transcription factors A (MRTF-A; syn. MAL, MKL1) and MRTF-B are widely expressed. MRTFs, but not myocardin, connect Rho family GTPases and actin dynamics with SRF-mediated transcription. MRTFs are also implicated in the development of myoepithelial cells, myofibroblast differentiation and fibrosis, cell motility and tumor metastasis. However, the regulation of MRTF expression itself is unknown.

Several miRNAs are specifically expressed in differentiating muscle cells, where they post-transcriptionally regulate gene expression and are required for the contractile phenotype. A prominent example is the miR-1, which is transcriptionally regulated by myocardin and in a negative feedback loop dampens the expression of contractile proteins in smooth muscle cells. MiR-206 is also predominantly expressed in muscle. How these miRs affect MRTF-A dependent differentiation of smooth or skeletal muscle cells remains largely elusive.