The role of the miR-26 family in neurogenesis

• Applicants: Privatdozent Dr. Matthias Becker, since 10/2019; Professor Dr. Utz Fischer
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells ; Developmental Neurobiology
• Term: from 2014 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 255064092

The coordinated induction of a neuron-specific gene expression program is a critical step in the differentiation of neural stem cells (NSCs) into neurons. Neurogenesis is driven by the repressor element silencing transcription factor (REST), which prevents expression of neuron-specific genes in NSCs. Critical effector proteins of the REST complex are small phosphatases such as the Ctdsps (RNA polymerase II C-terminal domain small phosphatases). They dephosphorylate the C-terminal domain of RNA-polymerase II and hence reduce its activity on target genes. The gradual inactivation of REST in development, in contrast, leads to a neuron-specific gene expression program that ultimately induces neurogenesis. The spatio-temporal control of the REST-factor Ctdsp is therefore a critical step during neuronal differentiation. Our work in zebrafish revealed that the mRNA encoding Ctdsp2 is a target of the micro-RNA (miR)-26b. miR-26b-mediated repression of Ctdsp2 mRNA results in reduced REST activity and the initiation of neurogenesis. Of note, miR-26b is encoded in an intron of the Ctdsp2 primary transcript, thus providing the basis of an intrinsic negative feedback loop. We further showed that this feedback loop is inactive in NSCs due to an arrest of miR-processing at the precursor level but it becomes activated in the course of neurogenesis. In the past funding period we could show that a negative factor prevents processing of all members of the miR-26 family in murine embryonic stem cell (ESC)-derived neuronal precursor cells (NPCs). Furthermore, we employed an ESC differentiation paradigm to assess miR-26a1, -26a2- and -26b-specific functions for neural differentiation. In the upcoming funding period we will investigate the function of identified miR binding factors in the regulated processing of the miR-26 family and determine how they impact on the gene expression and differentiation program that ultimately leads to neuron formation.

• DFG Programme: Priority Programmes
• Subproject of: SPP 1738: Emerging Roles of Non-Coding RNAs in Nervous System Development, Plasticity and Disease
• Ehemaliger Antragsteller: Professor Dr. Albrecht M. Müller, until 10/2019 (†)