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.
Conclusions:
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.
