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Nasal Placode Development, GnRH Neuronal Migration and Kallmann Syndrome

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Nasal Placode Development, GnRH Neuronal Migration and Kallmann Syndrome

Hyun-Ju Cho et al. Front Cell Dev Biol.

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.

Keywords: GnRH; Kallmann syndrome; neurodevelopment; neuronal migration; olfactory placode; olfactory system.

Figures

FIGURE 1
FIGURE 1
Multiple components form the GnRH migratory bundle during development. (A) Immunocytochemistry staining of E14.5 mouse section. Brown, GnRH (black arrows); Blue, peripherin (marking olfactory axons). Axons and cells must travel through the cribriform plate at the NFJ (boxed area) (B) Immunocytochemistry staining of GnRH (black) and peripherin (brown) at the nasal forebrain junction (NF/J). (C) Staining of GnRH neurons (brown) and BLBP (blue nuclei, labeling OECs) on the migratory route. (D) Schematic of multiple components forming the GnRH migratory bundle in mouse at E14.5. GnRH neurons (blue) migrate along VNO/terminal nerve axons (black lines) into the forebrain. Other VNO sensory axons bundle with olfactory sensory axons (green) and OECs (pink) enter the olfactory bulb.
FIGURE 2
FIGURE 2
Development of the olfactory system. (A) Schematic of olfactory placode formation. Cell populations at the border of the neural plate: preplacodal ectoderm (green), anterior pituitary placode (orange), and pre-migratory neural crest cells (purple), migrate rostrally and intermix to form the olfactory placodes. (B–E) X-Gal staining on nasal sections of E9.5–E11.5 neural crest reporter mouse (Wnt1Cre/RLacZ) showing Wnt1 expression (blue) in cells within the invaginating olfactory pit (OP, arrowheads), olfactory epithelium (OE), vomeronasal organ (VNO) and throughout the nasal mesenchyme (NM) and respiratory epithelium (RE). (F) Immunocytochemistry staining of E11.5 OE showing GnRH neurons (brown) located at the border between the RE and developing VNO. (G) Schematic of olfactory neurogenesis. Cell types in the OE can be identified by expression of specific factors, which direct cells to remain as cycling progenitors or to undergo neuronal differentiation to form sensory and/or GnRH neurons (Adapted from Whitlock et al., 2006; Forni et al., 2011).
FIGURE 3
FIGURE 3
Nasal explant model and migration assay. (A) Picture of E11.5 mouse embryo showing the location of the nasal pits (NP). (B) Schematic of a nasal explant after 4 days in vitro (div); nasal midline cartilage (NMC) and olfactory/VNO epithelium (NPE). GnRH neurons (black dots) migrate out of the nasal pit, toward the NMC, and then into the explant periphery. (C) 4div explant stained for peripherin (blue, marking olfactory axons) and GnRH (brown) (D) 4div explant stained for GnRH (blue) and SOX10 (brown, marking olfactory ensheathing cells nuclei). Boxed areas are magnified in panels (C1,D1), respectively. (E) Example of migration assay using a 4div nasal explant. GnRH cell movement is recorded within a 30 min time frame. , nucleus location of GnRH neuron; Black line, linear distance moved after 30 min.
FIGURE 4
FIGURE 4
Human-mouse GnRH distribution plot and molecules affecting GnRH neuronal migration. (A) Plot showing percentage of GnRH neurons that reside in nose/OB area between human (orange bars) and mouse (blue bars) at five developmental windows. CS: carnegie stage, GW: gestation week, E: embryonic stage. Data adapted from Casoni et al. (2016) and Wray et al. (1989b). (B) Schematic showing a GnRH neuron (blue) along the olfactory axon bundles (green), which are ensheathed by OECs (beige). Categories of axon outgrowth cues (green box), migration attraction gradients cues (red box) and ECM adhesion molecules (blue box) are indicated. Actin/microtubule interactions and actomyosin contractions (pink boxes) occur at the leading process and the trailing process of the migrating GnRH neuron.
FIGURE 5
FIGURE 5
Protein–protein interaction network in known genes of KS. The diagram shows known and predicted interactions among KS causative genes listed in Table 2, created using String software version 11.0 with minimal confidence score of 0.4. Total 87 lines (interactions) appeared across 25 nodes. The colored nodes symbolize proteins which clustered by MCL algorithm. The thickness of the line represents confidence of protein–protein associations (with score 0.4, 0.7, and 0.9, relatively). Solid line, interactions within a cluster; Dotted line, interactions between clusters.
FIGURE 6
FIGURE 6
Protein–protein interaction network in known genes of KS and their interacting partners. The diagram shows known and predicted interactions among KS causative genes and their interacting proteins, created using String software version 11.0 with minimal confidence score of 0.4. Total 227 lines (interactions) appear across 63 nodes (25 known factors of KS and 38 additional interacting proteins). The colored nodes symbolized proteins which clustered by MCL algorithm. The thickness of the line represents confidence of protein–protein associations. Solid line, interactions within a cluster; Dotted line, interactions between clusters. Abbreviations for 38 proteins interacting with known KS factors: ARMCX3, Armadillo repeat-containing X-linked protein 3; CBL, E3 ubiquitin-protein ligase CBL; CRBN, Protein cereblon; ESYT2, Extended synaptotagmin-2; FGF1, Fibroblast growth factor 1; FGF19, Fibroblast growth factor 19; FGF21, Fibroblast growth factor 21; FGFR1OP, FGFR1 oncogene partner; FGFR1OP2, FGFR1 oncogene partner 2; FLRT1, Leucine-rich repeat transmembrane protein FLRT1; FRS2, Fibroblast growth factor receptor substrate 2; GAB1, GRB2-associated-binding protein 1; GAS6, Growth arrest-specific protein 6; IRS4, Insulin receptor substrate 4; KL, Klotho; LPHN3, Adhesion G protein-coupled receptor L3; LRIT3, Leucine-rich repeat; NEDD4, E3 ubiquitin-protein ligase NEDD4; NIPBL, Nipped-B-like protein; NPTN, Neuroplastin; PAX3, Paired box protein Pax-3; PHIP, PH-interacting protein; PIK3R1, Phosphatidylinositol 3-kinase regulatory subunit alpha; PLCG1, 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1; PLXNA2, Plexin-A2; PLXNA3, Plexin-A3; PLXNA4, Plexin-A4; PLXNC1, Plexin-C1; PLXND1, Plexin-D1; ROBO1, Roundabout homolog 1; SHB, SH2 domain-containing adapter protein B; SP8, Transcription factor Sp8; SP9, Transcription factor Sp9; STAT3, Signal transducer and activator of transcription 3; STAT5A, Signal transducer and activator of transcription 5A; TRIM35, Tripartite motif-containing protein 35; UNC5D, Netrin receptor UNC5D; ZNF609, Zinc finger protein 609.
FIGURE 7
FIGURE 7
Expression level of genes causing KS vs. nIHH in OSN, OEC, and GnRH neurons. Genes related to KS (magenta) and genes only related to nIHH (blue) are plotted according to their expression level (FPKM) in the three different cell types. The gene expression values are gathered from previous studies and GEO database and compared in OSN (GSE53793), OEC (GSE69312) and GnRH neuron (Burger et al., 2018). The mean expression level and SD of gene group is represented as same color on the scattered plot.

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References

    1. Abraira V. E., Hyun N., Tucker A. F., Coling D. E., Brown M. C., Lu C., et al. (2007). Changes in Sef levels influence auditory brainstem development and function. J. Neurosci. 27 4273–4282. 10.1523/jneurosci.3477-06.2007 - DOI - PMC - PubMed
    1. Aguillon R., Batut J., Subramanian A., Madelaine R., Dufourcq P., Schilling T. F., et al. (2018). Cell-type heterogeneity in the early zebrafish olfactory epithelium is generated from progenitors within preplacodal ectoderm. eLife 7:e32041. 10.7554/eLife.32041 - DOI - PMC - PubMed
    1. Aksglaede L., Sorensen K., Petersen J. H., Skakkebaek N. E., Juul A. (2009). Recent decline in age at breast development: the Copenhagen Puberty Study. Pediatrics 123 e932–e939. 10.1542/peds.2008-2491 - DOI - PubMed
    1. Albuisson J., Pecheux C., Carel J. C., Lacombe D., Leheup B., Lapuzina P., et al. (2005). Kallmann syndrome: 14 novel mutations in KAL1 and FGFR1 (KAL2). Hum. Mutat. 25 98–99. 10.1002/humu.9298 - DOI - PubMed
    1. Allen M. P., Linseman D. A., Udo H., Xu M., Schaack J. B., Varnum B., et al. (2002). Novel mechanism for gonadotropin-releasing hormone neuronal migration involving Gas6/Ark signaling to p38 mitogen-activated protein kinase. Mol. Cell. Biol. 22 599–613. 10.1128/mcb.22.2.599-613.2002 - DOI - PMC - PubMed

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