(Vienna, 29-10-2024) An international study led by MedUni Vienna has identified the transcription factor ONECUT3 as a regulator of the development of neurons in the hypothalamus. Transcription factors such as ONECUT3 are proteins that control the activity of genes. The hypothalamus is a region of the brain that acts as an interface between the brain and body through hormone production, to control metabolism, growth, parenting and others. The research results can improve the understanding of how the manifold hypothalamic neurons gain functional specificity, and were recently published in "Nature Communications".
As part of the study, the research team co-led by Erik Keimpema and Tibor Harkany from MedUni Vienna's Center for Brain Research found that ONECUT3 changes the expression of genes that regulate how neurons acquire their complex morphologies and connect to one another. The team found that this transcription factor ensures that the timing of the placement and morphological development of hypothalamic neurons, that is their gaining specific shape for adequate connectivity, is in good time. ONECUT3 is powerful to switch genes on or off in neurons that affect survival, and the growth of a specific “polarized” shape with long processes, thereby influencing how the cell develops and which functions it assumes.
Through a combination of single-cell RNA sequencing - a method used to analyze the activity of genes in individual cells - and cell culture experiments involving the activation of ONECUT3, the research team showed that ONECUT3 primarily influences how neurons produce their long processes ("neurites") through which they connect to other neurons, nearby or far away, to transmit signals in the nervous system. In particular, ONECUT3 was shown to affect the activity of neuron navigator-2 (NAV2), a protein that changes the physical "building blocks" in these processes, termed cytoskeleton. In living organisms, the inhibition of ONECUT3 lowered NAV2 levels and activity, resulting in shorter processes, and a reduced ability for the cells to couple to one another. Thus, information transfer between neurons was reduced. Moreover, in nematodes, tiny worms that are broadly used in experimental research for their simple genetic make-up, the absence of their only proto-ONECUT gene impaired the neurites of sensory neurons that the worms use to navigate in their environment. Consequently, worms lacking ONECUT were unable to orient themselves any longer.
The studies also showed that ONECUT3 function was maintained throughout the evolution of the animal kingdom: "We found it in the hypothalamus of animals such as naked mole rats, fruit bats, sheep, mouse lemurs, and humans," reports lead author Erik Keimpema from MedUni Vienna's Center for Brain Research. "We were also able to establish that ONECUT3 is not only responsible for differentiation, i.e. development into certain cell types, but also for the structural adaptability of nerve cells," adds first author Maja Zupančič, also from MedUni Vienna's Center for Brain Research.
"Our findings advance understanding of the development processes the brains of mammals use for sets of neurons whose functions sustain life. ONECUT3 dysfunction seems lethal, giving a powerful example how a single tiny molecule can have profound effects and whose dysfunction could be so detrimental," says study leader Tibor Harkany, summarizing the relevance of the study.
Publication: Nature Communications
Concerted transcriptional regulation of the morphogenesis of hypothalamic neurons by ONECUT3.
Maja Zupančič, Erik Keimpema, Evgenii O. Tretiakov, Stephanie J. Eder, Itamar Lev, Lukas Englmaier, Pradeep Bhandari, Simone A. Fietz, Wolfgang Härtig, Estelle Renaux, Andreas Villunger, Tomas Hökfelt, Manuel Zimmer, Frédéric Clotman & Tibor Harkany
DOI: 10.1038/s41467-024-52762-z
https://www.nature.com/articles/s41467-024-52762-z
The study was funded by the Austrian Science Fund (FWF, P 34121-B;), the Swedish Research Council (2023-03058), the Swedish Brain Foundation (Hjärnfonden, FO2022-0300), the Novo Nordisk Foundation (NNF23OC0084476) and the European Research Council (FOODFORLIFE, ERC-2020-AdG-101021016).