1. European Research Network, GDRE EARLY PROGRAMMING OF MODERN DISEASES, EPMD GnRH-1 Neuronal Migration Paolo Giacobini 1. Unité Inserm 837, Centre de recherche Jean-Pierre Aubert Equipe 2, Développement et plasticité du cerveau postnatal, Lille, France 2. Dept. Human and Animal Biology, Lab. Neurobiology, University of Turin, Italy

2. GnRH neurons are the final common pathway through which the brain regulates the release of gonadotropins (LH, FSH) from the pituitary. Sisk and Foster, 2004

3. It begins in the olfactory placode…

4. OP Steps of GnRH-1 migratory process in normal condition Step 1 Step 3 Hyp ME Step 4 AOB Step 2 Guidance of the axonal/migratory pathway is an important prerequisite for establishment of the adult-like GnRH-1 cell distribution

5. IHH and Kallmann syndrome 1856 first known report of the syndrome small genitals; absence of puberty absent sense of smell To date, five KS genes have been identified, namely, FGFR1, FGF8, PROKR2, PROK2 and KAL-1. Mutations in these genes, however, only account for approximately 30% of all KS cases, suggesting that other genetic pathways might be relevant for this pathogenesis. A major focus of my research is to identify these molecules.

6. Rate of migration PSA N-CAM (Polysialic Acid; Hu H., 1996) GABA (Fueshko et al., 1998, Bless et al., 2000; Heger et al., 2003) Glutamate (Simonian and Herbison, 2001) CCK (Giacobini et al., 2004) Direction NETRIN (Schwarting et al., 2001; 2004) REELIN (Cariboni et al., 2005) SDF-1 (Schwarting et al., 2006) Semaphorin 3A and 3F (Cariboni et al., 2007) HGF/SF (Giacobini et al., 2002; 2007) Semaphorin 4D (Giacobini et al., 2008). Factors modulating GnRH-1 neuronal development Migration GABA (Moore et al., 2002), CCK (Giacobini and Wray, 2007), Kisspeptin (Constantin et al., 2008) Neuronal activity Activity

7. Rationale of the research Our combination of approaches will generate a novel framework to understand how the hypothalamic-pituitary-gonadal axis connectivity is established during normal and pathological development. Combining mouse genetics, ex vivo manipulations and imaging techniques, we plan to: i)Study the molecular mechanisms controlling the specification and migratory routes of GnRH-1 cells in vivo; i)understand the nature of GnRH-1 cells interactions with olfactory axons as well as their role in the correct targeting to their final destination areas; i)identify novel candidate genes which might be responsible for the onset of hypogonadotropic hypogonadisms in humans