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Glial-Puberty Report Summary

Project ID: 659474
Funded under: H2020-EU.1.3.2.

Periodic Reporting for period 1 - Glial-Puberty (The role of Glial cells in the control of puberty)

Reporting period: 2016-09-01 to 2018-08-31

Summary of the context and overall objectives of the project

Puberty, a key developmental period when the reproductive capacity is attained and sexual and somatic maturation completed, is under the control of a complex series of regulatory mechanisms that are sensitive to endogenous factors and environmental cues. However, characterization of the neuro-hormonal basis of puberty remains incomplete. A wealth of evidence has demonstrated the existence of reciprocal communications between glial cells and neurons; glial cells having an essential role in regulation of the functional activity of the nervous system. In this context, it is well established that glial cells play an important role in neuroendocrine regulation and participate in sexual differentiation of neuronal connectivity of brain regions involved in the control of puberty. Our studies have demonstrated that kisspeptins induce changes in markers of glial cell activity. Based on this data, the aim of this proposal was to provide better knowledge of the role of glial cells in the control of puberty and their interplay with kisspeptins, as major gatekeepers of puberty onset in mammals. To this end, we have used genetically modified (GM) models generated by the host laboratory, which allow the study of direct effects of kisspeptins on glial cells. In addition, we have generated a mouse model with deletion of Gpr54 (kisspeptin receptor) only in glial cells, to define their precise role in the control of puberty.
This project has implemented a systems biology approach, involving the use of different animal models (including GM mouse lines) and diverse and complementary analytical procedures. The proposed combination of novel methodological and analytical procedures, including GM mice and neuroanatomical analysis coupled to thorough validation by expression and functional studies, is considered very powerful. The information generated herein has been of physiological and pathophysiological relevance, as it has contributed to broaden our understanding of the basic role of glial cells in the control of pubertal maturation and fertility, and of the role of kisspeptin signaling in this phenomenon. In doing so, the results of this project will also help elucidate the putative mechanisms of reproductive dysfunction linked to metabolic stress. Moreover, the high throughput studies carried out in this action has released new knowledge about the implication of tumour-related genes in kisspeptin-dependent pathways altered mice models, which will lead substantial involvement in the knowledge about aggressive brain tumor development.

The specific objectives, animal models and research methodology implemented in the project are:

SO-1: To characterize Kisspeptin-dependent effects in glial cells using in vivo approaches.
SO-2: To develop a genetically-modified mouse model with selective lacking Gpr54 in astrocytes to assess the relevance of glial kisspeptin actions on puberty onset.

1. Kisspeptin receptor is expressed in a functional way in rodent and human astrocytes.
2. The number of astrocyte-dependent synapses are altered in the hypothalamus in mice model with kisspeptin signalling altered.
3. The communication between astrocytes and the Kisspeptin signalling pathway is mediated directly by Gpr54.
4. The role of the kisspeptin receptor (Gpr54) in astrocytes in term of puberty onset is being clarified using GM mice and will be finished soon.
5. The implementation of this project has shown for the first time not only a new receptor (Kisspeptin receptor – Gpr54) expressed in glial cells and its role in puberty onset, but also new data about the putative role of kisspeptins regulating tumor and cancer pathways.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

The project aims to identify new downstream effectors of kisspeptin action in the hypothalamus, as putative molecular transmitters for their activational roles on puberty. For this proposal, proteomic analysis for identification of global changes in protein expression patterns induced by kisspeptins were implemented. The results documented two new biological pathways that appeared significantly altered: i) Synaptic plasticity and glial cell markers; and ii) Tumor and cancer-related pathways, both of them have not been studied before and provide the conceptual basis for a new research line.
In this sense, we found for the first time that the kisspeptin receptor (Gpr54) is expressed in rodent and human astrocytes. All the experiments designed were focused to understand the role of kisspeptin receptor (Gpr54) in the glial cell.
Overview of main results:
1. Kisspeptins induce changes in glial cells to alter the number of excitatory and inhibitory synapses in the hypothalamus.
2. The actions of kisspeptins on glial cells are mediated directly by his receptor (Gpr54).
3. The deletion of Gpr54 in astrocytes doesn´t alter the reproductive physiology, at least in physiological conditions.
4. Deviations from original proposal: Tumor related genes are regulated by kisspeptins in hypothalamus.
Exploitation and dissemination of the results:
The results have been presented, mainly via oral communications in American Society of Endocrinology, Cambridge Neuroscience, European Cooperation in Science and Technology, LARC-Neuroscience Network, and in the biannual meeting on Kisspeptins.
Due to the innovative nature of this proposal and the time frame of working with transgenic mice, the results obtained in the last two years have not yet been published. We are organizing all data in figures to be published during the next few months. It is important to note, that the implementation of this project has shown for the first time not only a new receptor (Kisspeptin receptor – Gpr54) expressed in glial cells and its role in puberty onset, but also new data about the putative role of kisspeptins regulating tumor and cancer pathways.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The gradual decline in the age of puberty in girls, as well as the increasing rate in the brain cancer incidence, are worrisome trends that have been reported across Europe; phenomena that are causing major concerns and attracting considerable attention not only among the scientific community but also in the lay public. Notably, the growing incidence of alterations affecting the reproductive axis has been linked to the raising prevalence of infertility and childhood obesity. The GLOBAL OBJECTIVE of this proposal is to provide an integral characterization of the role of glial cells in the physiological control of puberty, and their role in mediating Kisspeptin actions in this phenomenon. The main results after the implementation of this action have been the discovery of two new biological kisspetin-dependent pathways: i) synaptic plasticity and glial cell markers, which have been studied in detail in this MSCA; and ii) tumor and cancer related pathways, which have not been studied before. The advances in term of synaptic plasticity mechanism implicated in the control of kisspeptins action will be critical to characterize the role of kisspeptins in our brain. Moreover, glioblastoma and other glial related tumors urgent improving the pathophysiological knowledge to develop new treatment strategies. In this scenario, it is anticipated that, the dissection of the specific pathways and mechanisms involved in setting of a novel kisspeptins/TRGs system will have an enormous impact in terms of Scientific Knowledge and Translational Medicine.

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