ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2019) 65 OC6.4 | DOI: 10.1530/endoabs.65.OC6.4

Kallmann syndrome-associated WDR11 regulates primordial germ cell development

Ji Young Lee, Yeon Joo Kim, Paris Ataliotis, Dorothy Bennett, Nigel Brown & Soo Hyun Kim

St. George’s Medical School, University of London, London, UK

The primary cilium, a non-motile microtubule-based organelle protruding from most vertebrate cells, serves as a specialized compartment for signal transduction. Any disruption of ciliogenesis leads to ciliopathy-spectrum disorder with multiple signalling failure in development and homeostasis. Several ciliopathies including Bardet–Biedl syndrome associate with infertility and hormone imbalances, but the role of primary cilia in reproductive disorders is not clear. Congenital hypogonadotropic hypogonadism (CHH) and Kallmann syndrome (KS) are genetic disorders defined by delayed/arrested puberty and infertility. We previously identified WD-repeat protein 11 (WDR11) was mutated in CHH/KS. Our recent studies demonstrated that WDR11 is required for ciliogenesis and Hedgehog (Hh) signalling. Animal models lacking WDR11 exhibit defective cilia and dysregulation of the Hh signal pathway. This places KS/CHH in the human ciliopathy spectrum. Our current study further demonstrates that the reduced fertility of WDR11-deficient individuals may be due to the defective migration of the pluripotent primordial germ cells (PGCs), resulting in a reduced number of germ cells present in the gonads at birth. PGCs are the founders of gametes. During early gonadogenesis, PGCs migrate towards the developing genital ridges where they integrate with the surrounding mesenchyme before undergoing sex differentiation. By live-imaging of mouse embryo slice cultures, we confirmed the loss of Wdr11 caused a reduced migration capacity of PGCs without affecting their directionality. Hh signalling agonist/antagonist could alter PGC motility. Interestingly, despite their sensitivity to Hh signalling, PGCs are naturally un-ciliated. The somatic cells surrounding the PGCs are widely ciliated, suggesting that the soma may provide the key signals important for PGC migration. Our work has identified the PGC migration defects as one of the underlying causes of KS/IHH, implicating a scenario of primary hypogonadism. Based on these findings, consideration of differential diagnosis and treatment regime can be established for gonadotrophin non-responders.

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