Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.775349
Title: Dual function of WDR11 in the pathogenesis of hypogonadotrophic hypogonadism
Author: Lee, Ji-Young
ISNI:       0000 0004 7962 5256
Awarding Body: St George's, University of London
Current Institution: St George's, University of London
Date of Award: 2019
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Abstract:
Kallmann Syndrome (KS) and normosmic hypogondotropic hypogonadis(nHH) are human genetic disorders classically defined by gonadotrophin-releasing hormone deficiency leading to dysfunction of the Hypothalamic-Pituitary-Gonadal axis and presenting as complete or partial failure of pubertal development. WDR11 was previously identified as one of the underlying genetic loci for KS/nHH, but the function of WDR11 remains largely unknown. Preliminary data in zebrafish showed that knockdown of wdrll caused a disruption in the development of primordial germ cells (PGCs). The WDR11 interacting partner EMX1 is involved in organogenesis of the brain and gonads, and is a downstream target of HH signalling. Thus, we hypothesise that WDR11 may regulate PGC development through the Hedgehog (HH) signal pathway. Consistent with this hypothesis, I found that W drll, Emxl/2 and other HH signal pathway genes are expressed in the mouse PGC migratory niche. Furthermore, the genital ridge area of Wdr11 gene-trap knockout (KO) mouse embryos showed reduced expression of these genes. Utilising the StellaGFP transgenic mouse, I investigated the role of Wdrll in the migration of PGC s, by various complementary approaches including live imaging of embryo slice cultures. Results show that W drll KO embryos contain ectopic PGCs, likely due to observed reduction in the migration (speed, distance) and proliferation capacity of PGCs, resulting in a diminished number of germ cells arriving in the gonads. Using the same method, treatment with HH antagonist or agonist inhibited or enhanced PGC motility, respectively without affecting the directionality of migration, showing that HH signalling has a critical role in PGC migration. Since W DR11 is also important for ciliogenesis, the presence of primary cilia was analysed in the PGC migratory niche, by immunofluorescence. Results show that primary cilia are absent on the PGC but are present on somatic niche cells, which was necessary for normal PGC migration. These data provide novel insights into the developmental processes of PGCs in mammals, and suggest an important role of Wdr11 and the primary cilia-dependant HH signalling pathway within the PGCs.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.775349  DOI: Not available
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