Defining the role of SEMA3E and PLXND1 in the GnRH neuron system that regulates sexual reproduction in mammals

During foetal development, gonadotropin releasing hormone (GnRH) neurons are born in the nose and must migrate to the hypothalamus, a brain structure in which these neurons make contact with blood vessels to secrete the hormone they produce into the general circulation. Mistakes made during the establishment of the GnRH neuron system impair hormone secretion and therefore delay puberty and sexual reproduction, for example in the condition Kallmann Syndrome. Accordingly, understanding how the GnRH neuron system forms provides important inside into the origin of genetic disorders such as Kallmann Syndrome and help identify novel targets for mutation screening in patients seeking genetic diagnosis and treatment. For example, the early diagnosis of genetic defects that cause GnRH neuron deficiency allows timely treatment with hormone therapy to ameliorate or prevent the onset of symptoms. However, only some of the genetic causes have been identified so far. Recently, we discovered that a signalling molecule called VEGF-A promotes the survival of GnRH neurons when they migrate through the nose to reach the brain. We also discovered that a different signalling molecule called SEMA3A is essential to establish the neural 'highway' on which migrating GnRH neurons travel to reach the brain. Our findings underpinned subsequent studies of others, who identified genetic mutations that impair SEMA3A function in patients with Kallmann Syndrome. We now seek funding to study a related semaphorin known as SEMA3E and its receptor PLXND1 in the GnRH neuron system, because our pilot experiments suggest that the interaction of these two molecules is essential at later stages of GnRH neuron development. This research will significantly enhance our understanding of the GnRH neuron system and advance the development of novel tests for patients seeking genetic diagnosis for reproductive disorders.

Gonadotropin releasing hormone (GnRH) neurons are neuroendocrine cells that arise in the nasal placodes during embryogenesis, but migrate to the hypothalamus, where they regulate puberty and sexual reproduction by secreting GnRH into the circulation. Studying the generation, migration, survival and neurite projection of GnRH neurons provides an excellent model system to elucidate the molecular and cellular mechanisms of neural development and the formation of neuroendocrine systems that regulate physiological functions in mammals. We have recently identified two different signalling pathways that are essential for the normal migration versus survival of a significant proportion of GnRH neurons during their migration through the nose. Moreover, we found that the joint loss of both pathways caused a catastrophic failure of assembling the GnRH neuron system. Our new pilot data show that PLXND1, a molecule known best for its role as SEMA3E receptor in blood vessel patterning and axon guidance, is similarly important for normal GnRH neuron development. We now wish to extend these findings to define the precise roles of PLXND1 and its ligand SEMA3E in the GnRH neuron system and assess the impact of losing this signalling pathway on GnRH cell behaviour, gonad development and fertility. We will use a combination of expression, genetic, functional and biochemical assays to identify and distinguish possible roles for SEMA3E and PLXND1 in GnRH neuron generation, migration, survival and axon projection. The proposed programme of work will advance significantly our understanding of the mechanisms that establish the GnRH neuron system and provide fundamental information on a signalling pathway affected in Kallmann Syndrome.

Academia: This project will significantly enhance our knowledge of the developmental processes that establish functional brain wiring patterns and will be specifically important for national and international researchers in the areas of neurodevelopment, molecular genetics, endocrinology and sexual reproduction. In the medium term, this research will also benefit translational researchers aiming to design new clinical tests for inherited forms of infertility. Beyond their interest to the academic community, the results will impact on several other identifiable beneficiaries, as listed below.

Commercial private sector and clinical services: Because this work will identify novel functions for semaphorin signalling pathways, the results are likely to be of interest to the commercial sector involved in developing diagnostic tests for patients with neurological or reproductive disorders, as they may be able to capitalise on this new knowledge. Accordingly, this project is likely to contribute new knowledge that will lead to more translational research in the medium term. In the long term, the academic knowledge generated will benefit clinical medicine to impact positively on public health in the UK and abroad, both generally by expanding our knowledge base and specifically by advancing the generation of novel diagnostic tests to improve health and well-being.

General public: An immediate impact of this project is its opportunity to raise awareness and understanding of science and research through public dissemination of novel findings and explaining their significance. Knowledge of the developmental processes that promote neurodevelopment and normal sexual reproduction is key to understanding how we function as adult human beings. Learning about the normal mechanisms that control these processes will also improve the public's understanding of the origins of reproductive disorders, an area of high clinical need and social importance. These topics will be incorporated in outreach activities to engage with the public about this work, for example by providing work experience and giving lectures to secondary school students.

UK and International Research Base: By endowing researchers with both project specific and transferable skills, this project will lead to highly skilled workers that will benefit the UK's economic competitiveness. The project will also lead to new international collaborations and therefore enhance knowledge transfer and increase the international profile of our Universities.