From third ventricle to pituitary gland: regulatory RNA networks in post-transcriptional modulation of gene expression in neurosecretion

• Applicant: Andranik Ivanov, Ph.D.
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells ; General Genetics and Functional Genome Biology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 564170696

Regulatory non-coding RNAs (ncRNAs), such as miRNAs, enhancer RNAs, circRNAs, and long non-coding RNAs have been shown to fine-tune gene expression programs. De-regulation of ncRNAs has been associated with many human diseases, e.g. psychiatric and neurodegenerative disorders, brain tumors, and metabolic diseases. However, for many non-coding RNAs, the cell-type specific expression signatures are unknown, and the mechanisms of action remain elusive. Here, we propose to study ncRNAs in the context of the neuroendocrine system in hypothalamic ependymocytes residing in the third ventricle and hormone-producing cells derived from the pituitary gland which are central to metabolic and hormonal coordination. The dysfunction of these cells leads to serious physiological consequences and is a source of different kinds of disorders associated with neurodegeneration, reproductive disorders such as polycystic ovary syndrome or infertility, secondary thyroid diseases, or the development of tumors. This project hypothesizes that miRNA and circRNA contribute to gene expression regulation in the hypothalamic-pituitary axis in a cell-type and condition-dependent manner. Specifically, we aim (1) to determine the repertoire of regulatory RNAs in ependymal cells in steady-state and upon energy imbalance, (2) to discern the function of circRNA Cdr1as in ependyma, (3) to characterize miRNA and miRNA-mRNA networks in a cell-type-specific manner within the hypothalamic-pituitary-specific cells, namely tanycytes, gonadotropes, and thyrotropes. The latter will be performed both in steady-state and upon physiological challenges. The anticipated results will instruct about the extent of regulatory RNA influence on the transcriptome and molecular processes of a few populations of cells residing within the hypothalamic-pituitary gland axis of the brain. We will generate high-throughput information about miRNA, circRNA, and mRNA profiles in the aforementioned specialized cell populations of the neuroendocrine system. We will acquire detailed information on whether and how circRNA Cdr1as and miRNAs are involved in molecular pathways in studied cell types. The high-throughput transcriptomic data will be validated with single-molecule RNA imaging in the mouse tissues, functional studies, proteomics, and standard molecular and cellular biology techniques. Overall, we are motivated to create a vital data source for understanding cell-type specific and condition-dependent regulatory functions of ncRNAs and their influence on protein-coding genes in neurosecretion. This project will be possible to implement due to the joint forces of three laboratories from three different countries and of three different leading expertise: neuroanatomy/biology of the ventricular system (Swiss partner), RNA biology (Polish partner), and bioinformatics (German partner).

• DFG Programme: Research Grants
• International Connection: Poland, Switzerland
• Partner Organisation: Schweizerischer Nationalfonds (SNF)
• Cooperation Partners: Dr. Fanny Langlet, Ph.D.; Dr. Monika Piwecka