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Title: The role of the chemokine SDF-1 and its receptors CXCR4 and CXCR7 in the migration of GnRH neurons
Author: Memi, F.
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2013
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Reproduction in mammals is initiated and maintained by a small population of cells called Gonadotropin-releasing hormone (GnRH) neurons, scattered throughout the preoptic area and anterior hypothalamus. These neurons originate in the nasal placode, and migrate across the nasal compartment in association with olfactory, vomeronasal and terminal nerves to reach their targets in the hypothalamus. In humans, defective GnRH neuron migration results in gonadal dysfunction and subsequent infertility. As mutated genes identified so far in patients account for only 30% of the cases, many unknown genes involved in GnRH neuron development still need to be discovered. One of the molecules required for their early migration is the chemokine SDF-1 which is expressed in the embryonic nasal mesenchyme in an increasing rostral to caudal gradient, presumably guiding CXCR4-expressing GnRH neurons towards the forebrain. Mice lacking CXCR4, the receptor for SDF-1, exhibit defective GnRH neuron migration along with a significant reduction in number. This thesis focuses on the role of the more recently identified second SDF-1 receptor, CXCR7, in GnRH neuron development. A detailed analysis of the expression pattern of CXCR7 in the nasal region and comparison to that of its agonist (SDF-1) as well as CXCR4, was elucidated for the first time. CXCR7 was found to be expressed along the migratory path of GnRH neurons in the nasal region, but not by GnRH neurons or their guiding axons. The role of CXCR7 in GnRH neuron migration in vivo was assessed using transgenic mice deficient for this receptor. This analysis revealed that in these mice, many GnRH cells remained in the nasal compartment, clustering or found ectopically in the olfactory epithelium. Interestingly, CXCR4 was downregulated in CXCR7 defective mice, suggesting that CXCR7 affects GnRH migration indirectly, by regulating CXCR4 in a non-cell autonomous manner.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available