Loss of Kallmann syndrome-associated gene WDR11 disrupts primordial germ cell development by affecting canonical and non-canonical Hedgehog signalling

Abstract

Mutations of WDR11 are associated with Kallmann syndrome (KS) and congenital hypogonadotrophic hypogonadism (CHH), typically caused by defective functions of gonadotrophin-releasing hormone (GnRH) neurones in the brain. We previously reported that Wdr11 knockout mice show profound infertility with significantly fewer germ cells present in the gonads. To understand the underlying mechanisms mediated by WDR11 in these processes, we investigated the effects of Wdr11 deletion on primordial germ cell (PGC) development. Using live-tracking of PGCs and primary co-cultures of genital ridges (GR), we demonstrated that Wdr11-deficient embryos contained reduced numbers of PGCs which had delayed migration due to significantly decreased proliferation and motility. We found primary cilia-dependent canonical Hedgehog (Hh) signalling was required for proliferation of the somatic mesenchymal cells of GR, while primary cilia-independent non-canonical Hh signalling mediated by Ptch2/Gas1 and downstream effectors Src and Creb was required for PGC proliferation and migration, which was disrupted by the loss of function mutations of WDR11. Therefore, canonical and non-canonical Hh signalling are differentially involved in the development of somatic and germ cell components of the gonads, and WDR11 is required for both of these pathways operating in parallel in GR and PGCs, respectively, during normal PGC development. Our study provides a mechanistic link between the development of GnRH neurones and germ cells mediated by WDR11, which may underlie some cases of KS/CHH and ciliopathies.

Disorders of Sex Development in a Large Ukrainian Cohort: Clinical Diversity and Genetic Findings

“…The prepubertal testicular volume (<4 ml), low serum inhibin B concentration and a history of cryptorchidism are described as negative predictors of stimulating treatment response (41) as we observed in case 26, but in case 23 both treatment modalities (Follitropin alfa and HCG) were ineffective where only micro-orchidism was present. This suggests that a small testicular volume by itself can be considered as unfavorable predictor, which differs from published data (42) and 'primary' hypogonadism in GnRH non-responders with ANOS1 variants should not be excluded (43). However, two cousins with an ANOS1 LOF variant and with a history of either untreated cryptorchidism, small testicular volume (<4 ml) but normal AMH and inhibin B levels had a good response to HCG treatment.…”

Structural Insights into the Roles of PARP4 and NAD+in the Human Vault Cage

“…A third set of highly abundant genes in our pulldowns regulate cell migration and invasion (teal data points, Fig. 5), including TRO [30], one of the most abundant hits, as well as RACK1 [31], WDR11 [32], MICAL2 [33], and -the only gene in this group to inhibit cell migration -TCAF1 [34]. Finally, SLC25A1, a solute carrier, emerged as an interesting hit for its homology with another solute carrier that transports NAD + into the mitochondria [35].…”

Congenital hypothalamic hypogonadism — a Kallmann syndrome in boys. Clinical cases

“…Тому йому додатково призначили замісну терапію препаратами тестостерону (СЕТ, ТТ), що сприяло нормалізації вмісту в крові тестостерону з одночасним зменшенням об'єму яєчок та рівня в крові інгібіну В. Наявність таких ознак в анамнезі, як крипторхізм, передпубертатний об'єм яєчок (< 4 мл), низька концентрація інгібіну В у сироватці крові, описані як негативні предиктори відповіді на стимулювальне лікування [28], але у випадку пацієнтів 2 і 3 лікування лХГ виявилося успішним, незважаючи на наявність мікроорхідизму і крипторхізму, у пацієнта 1 лікування р-лФСГ та лХГ було неефективним у разі лише малого об'єму яєчок. Це свідчить про те, що мікроорхідизм сам по собі можна розглядати як несприятливий чинник у деяких пацієнтів, що суперечить опублікованим раніше даним [29]. Отже, наявність «первинного» гіпогонадизму не можна заперечити у пацієнтів, які не відповідають на лікування препаратами ГнРГ при СК [30].…”