Abstract
Congenital hypogonadotropic hypogonadism (CHH) is a condition characterized by absent puberty and infertility due to gonadotropin releasing hormone (GnRH) deficiency, which is often associated with anosmia (Kallmann syndrome, KS). We identified loss-of-function heterozygous mutations in anti-Müllerian hormone (AMH) and its receptor, AMHR2, in 3% of CHH probands using whole-exome sequencing. We showed that during embryonic development, AMH is expressed in migratory GnRH neurons in both mouse and human fetuses and unconvered a novel function of AMH as a pro-motility factor for GnRH neurons. Pathohistological analysis of Amhr2-deficient mice showed abnormal development of the peripheral olfactory system and defective embryonic migration of the neuroendocrine GnRH cells to the basal forebrain, which results in reduced fertility in adults. Our findings highlight a novel role for AMH in the development and function of GnRH neurons and indicate that AMH signaling insufficiency contributes to the pathogenesis of CHH in humans.
Highlights
Gonadotropin releasing hormone (GnRH) is essential for puberty onset and reproduction
We have recently shown that migratory gonadotropin releasing hormone (GnRH) neurons and developing vomeronasal/olfactory axons express Amhr2 in mammals (Cimino et al, 2016)
We investigated whether migratory GnRH neurons expressed Amh in addition to Amhr2
Summary
Gonadotropin releasing hormone (GnRH) is essential for puberty onset and reproduction. We have previously shown that GnRH neurons express AMHR2 from early fetal development to adulthood and that AMH stimulates GnRH neuronal activity and hormone secretion in mature GnRH cells (Cimino et al, 2016) We expand this information by demonstrating that GnRH cells express AMH during their migratory process, both in mice and human fetuses and we describe a novel role of AMH as a potent stimulator of GnRH cell motility. This study identified a novel embryonic role of AMH in the development and function of GnRH neurons and provides genetic evidence that disturbance of AMH signaling can contribute to CHH phenotype in humans
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