Nasal Placode Development, GnRH Neuronal Migration and Kallmann Syndrome

Abstract

The development of Gonadotropin releasing hormone-1 (GnRH) neurons is important for a functional reproduction system in vertebrates. Disruption of GnRH results in hypogonadism and if accompanied by anosmia is termed Kallmann Syndrome (KS). From their origin in the nasal placode, GnRH neurons migrate along the olfactory-derived vomeronasal axons to the nasal forebrain junction and then turn caudally into the developing forebrain. Although research on the origin of GnRH neurons, their migration and genes associated with KS has identified multiple factors that influence development of this system, several aspects still remain unclear. This review discusses development of the olfactory system, factors that regulate GnRH neuron formation and development of the olfactory system, migration of the GnRH neurons from the nose into the brain, and mutations in humans with KS that result from disruption of normal GnRH/olfactory systems development.

Association of olfactory neuropathy spectrum disorder and Wolff‐Parkinson‐White syndrome: A Report of a case

“…MRI can be helpful in the workup of cases of anosmia or hyposmia (congenital or new-onset), as MRI can evaluate the presence of the olfactory nerves Kallmann syndrome is the most common syndrome associated with congenital anosmia. 5,6 Kallmann syndrome is a rare disease and there is a high degree of genetic variation, and only approximately 40% of Kallmann syndrome is caused by known genetic mutations. A thorough description of the known mutations involved in Kallmann syndrome is beyond the scope of this case report, but has been well summarized and includes many gene loci, including the X-linked KAL1 (ANOS1) (accounting for approximately 10%-20% of Kallmann syndrome patients), FGFR1, FGF8, and many others.…”

“…A thorough description of the known mutations involved in Kallmann syndrome is beyond the scope of this case report, but has been well summarized and includes many gene loci, including the X-linked KAL1 (ANOS1) (accounting for approximately 10%-20% of Kallmann syndrome patients), FGFR1, FGF8, and many others. 5,6 The nasal placode is a source of forebrain GnRH cells, and the involvement of the GnRH pathway in both the reproductive and olfactory systems is thought to account for the common hypogonadotropic hypogonadism and anosmia seen in Kallmann syndrome. The olfactory placodes form in the ventrorostral area of the developing vertebrate brain and form from neural crest cells and non-neural ectoderm.…”

“…[1][2][3][4] Kallmann syndrome is a disorder characterized by hypogonadotropic hypogonadism and congenital absence of the olfactory bulbs and is likely the most well-known cause of congenital anosmia. 5,6 In this syndrome, patients present with lack of sexual development and delayed or absent puberty, as well as anosmia. Female patients may not undergo puberty until placed on exogenous hormones, for example, oral contraceptives.…”

The evolutionary origins of the vertebrate olfactory system

“…The GnRH1 neurons are key regulators of fertility as an essential part of the hypothalamic–pituitary–gonadal axis (HPG). These cells migrate along axons of the terminal nerve / olfactory pathways up to the forebrain where they settle inside the pre-optic and hypothalamic areas [ 25 ]. Once settled within the hypothalamus, GnRH1 neurons send their axons to the median eminence and secrete GnRH1 into the portal vessels, where it travels to the adenohypophysis [ 26 ].…”

“…The basal cells are stem cells used to constantly replenish the olfactory epithelium as they can differentiate into either OSNs or supporting cells. The MOS also contains the mucus-producing olfactory (Bowman's) glands whose proteinaceous secretion allows solubilization of odorants in the nasal cavity [ 25 , 34 ]. These cells are important for vertebrate olfactory system function but will not be the focus of this review as they are not easily compared between vertebrates and other chordates.…”