Axonal 7SK functions in motoneuron development and disease

• Applicant: Dr. Michael Briese
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 554960089

Motoneurons are highly polarized cells that extend their axons over long distances to connect to their target muscles. During motoneuron development, axonal mRNA transport critically contributes to the local synthesis of proteins required for axon growth and establishment of synapses. Failure of axonal mRNA localization can destabilize axons, which is an early pathological event in motoneuron disorders such as spinal muscular atrophy (SMA). The non-coding RNA 7SK is abundant in nuclei and regulates transcription activation of most genes. 7SK is highly structured and has been characterized in detail for its function as RNA scaffold that controls the activity of the nuclear P-TEFb complex. We have shown that, in motoneurons, 7SK is not only present in the nucleus but also localizes to axons indicating vital functions for axon growth and establishment of neuromuscular connections. In our proposed project, we would like to characterize the protein and RNA composition of axonal 7SK complexes from primary mouse motoneurons and human motoneurons differentiated from iPSCs. Furthermore, we will generate 7SK knockout (KO) iPSCs in order to characterize the consequences of 7SK loss for axon growth and maturation in human motoneurons. We will use transcriptome analysis and translation assays to identify transcripts whose axonal localization and local translation is mediated by 7SK transport particles. Finally, we will investigate whether defects in axonal 7SK-dependent processes contribute to pathomechanisms underlying SMA. We anticipate that the findings obtained throughout the project will not only reveal new axonal functions for 7SK, but also provide novel insights into RNA pathomechanisms underlying motoneuron disorders.

• DFG Programme: Research Grants