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Illuminating the terminal nerve: Uncovering the link between GnRH-1 neuron and olfactory development

ABSTRACT: During embryonic development, the olfactory placode (OP) gives rise to various populations of neurons; these include putative olfactory pioneer neurons, different neurons of unknown identity and function, cells of the terminal nerve, and the Gonadotropin-releasing hormone-1 (GnRH-1) neurons. In mice, the GnRH-1 neurons are first detectable in the developing olfactory system around mid-gestation. From here, the GnRH-1 neurons migrate, along the axons of the terminal nerve (TN), to various regions of the developing brain. Once in the brain, the GnRH-1 neurons play a central role in controlling the hypothalamic-pituitary-gonadal (HPG) axis. Early migratory neurons forming from the olfactory placode have been proposed to play a vital role in inducing olfactory bulb morphogenesis. Kallmann syndrome is a condition characterized by defective development of the olfactory system and infertility. Murine studies have demonstrated the critical role of the Prokineticin 2-Prokinteicin Receptor 2 pathway in olfactory bulb morphogenesis and GnRH-1 neuronal migration. Loss-of-function Prokr2 mutations cause both Kallmann syndrome associated with bulb agenesis and normosmic idiopathic hypogonadotropic hypogonadism (nIHH). Following Prokr2 expression and lineage tracing, we found that Prokr2 is not expressed by the cells of the developing olfactory bulb but by migratory putative pioneer/terminal nerve neurons. Performing single-cell-RNA-sequencing, we identified genes enriched in the migratory cells of the putative terminal nerve. By integrating genetic lineage tracing and single-cell transcriptomics, we identified previously undescribed populations of migratory neurons that appear to be enriched in the expression of several genes related to olfactory defects, GnRH migratory deficiencies and infertility.

ORGANISM(S): Mus musculus

PROVIDER: GSE234871 | GEO | 2024/03/11

REPOSITORIES: GEO

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Project description:The olfactory sensory system is formed by the coordinated morphogenesis and differentiation of the peripheral olfactory epithelium (OE) and the anterior forebrain. At early stages, immature olfactory receptor neurons (ORN) elongate their axons to penetrate the brain basement membrane, contact and form synapses with projection neurons of the olfactory bulb primordium. Axonal elongation is accompanied by migration of the GnRH+ neurons, followed by their ingression in the septo-hypothalamic area of the forebrain. This process is specifically impaired in the KallmannM-bM-^@M-^Ys syndrome (KS), a disorder characterized by anosmia and central hypogonadism. A set of transcription factors are master regulators of olfactory connectivity and GnRH neuron migration. We explored the transcriptional network underlying this process, by profiling the OE and adjacent mesenchyme at distinct embryonic ages. We also profiled the OE from embryos null for Dlx5, a homeogene essential for olfactory development, that causes a KS-like phenotype when deleted. We also applied analysis of conserved co-expression to integrate the obtained data with information on KS disease genes. The prevalent categories of genes differentially expressed during development are neuronal differentiation, extracellular remodelling and cell adhesion. From the analysis of Dlx5 mutant tissues we identify about 120 genes with a prevalence of intermediate filaments, cell signalling, epithelial and neuronal differentiation. Filtering for true OE expression and for the presence of Dlx5 binding sites, yielded twenty genes, of the following categories: 1) transmembrane adhesion/receptor molecules, 2) axon-glia interaction molecules, 3) synaptic proteins, 4) scaffold/adapter for signalling molecules. To functionally analyze these genes in vivo, we used three zebrafish fluorescent reporter zebrafish strains, in which we monitored early phases of olfactory/GnRH development upon gene downmodulation. The depletion of three (of five) Dlx5 targets affected axonal extension and targeting, while two (of two) altered GnRH neuron position and neurite organization. In one experiment we compare the olfactrory sensory epithelium from wild-type embryos, at three times of development, i.e. E11.5, E12.5 and E14.5. In a second experiment we compare the olfactory sensory epithelium from wild-type embryo with that from Dlx5 knock-out embryos, at the age E12.5

Project description:Olfactory ensheathing cells are one of the few central nervous system regenerative cells discovered so far. It is characterized by its lifelong nerve regeneration function, and it can also release a variety of neurotrophic factors and neural adhesion molecules. It is considered to be the glial cell with the strongest myelination ability. Olfactory ensheathing cells and Schwann cells have phenotypes in common, they can promote axon regeneration(R. Doucette, 1995). Olfactory ensheathing cells have the characteristics of Schwann cells and astrocytes, but the overall performance tends to be the former, which has two unique characteristics. First, it exists not only in the peripheral nerves (Schwann cells), but also in the central nervous system (astroglia); second, the olfactory mucosa has the ability to regenerate life-long, including human olfactory ensheathing cells(J. C. Bartolomei and C. A. Greer, 2000). Regeneration is a process in which olfactory ensheathing cells participate in efficient regulation, although the specific mechanism is not yet clear. Olfactory ensheathing cells are different from astrocytes and Schwann cells, but at the same time have the characteristics of these two cells(S. C. Barnett, 2004), like Schwann cells help axon growth, but more than Schwann cells It can make axons grow long distances, that is, it has stronger migration(A. Ramon-Cueto et al., 1998); there are also astrocytes that have a nutritional effect on the survival of neurons and the growth of axons, but olfactory ensheathing cells can also wrap neurons forms myelin sheath to support the growth of nerve processes(R. Devon and R. Doucette, 1992; J. Gu et al., 2019). There are two characteristics that make olfactory ensheathing cells the best choice for the treatment of neurological diseases(S. C. Chiu et al., 2009; J. Kim et al., 2018; M. Abdel-Rahman et al., 2018). Olfactory ensheathing cells are gradually used to treat spinal cord injuries and have shown amazing effects(J. C. Bartolomei and C. A. Greer, 2000; K. J. Liu et al., 2010; R. Yao et al., 2018). Olfactory ensheathing cells that have been used in research are usually derived from the olfactory bulb(E. H. Franssen et al., 2007), but it is easier to obtain olfactory ensheathing cells from the olfactory mucosa in clinical practice(M. Ryszard et al., 2006), so the difference between the olfactory ensheathing cells from the olfactory bulb and the olfactory mucosa There are more and more studies(B. M. U. et al., 2007), and previous studies have shown that they not only have many similar functions, but also have many differences(M. W. Richter et al., 2005; L. Wang et al., 2014; K. E. Smith et al., 2020). Because olfactory ensheathing cells derived from the olfactory bulb are not easy to obtain, olfactory ensheathing cells derived from the olfactory mucosa have become the focus of attention. Although we know that olfactory ensheathing cells from two sources have nerve repair functions, it is not clear why the two different sources of olfactory ensheathing cells have different therapeutic effects. Nicolas G. once studied that the genetic difference between the two cells and found that there are many genes related to wound repair and nerve regeneration(G. Nicolas et al., 2010). We have reason to guess that olfactory ensheathing cells from these two sources will also have a large difference in protein level. Our research group wants to use the current mature transcriptome and proteomic sequencing technologies to explore the difference between olfactory ensheathing cells from the olfactory bulb and olfactory mucosa, and explain why the two sources of olfactory ensheathing cells shows different therapeutic effects, hope to provide a new theoretical basis for future clinical treatment.

Project description:The olfactory sensory system is formed by the coordinated morphogenesis and differentiation of the peripheral olfactory epithelium (OE) and the anterior forebrain. At early stages, immature olfactory receptor neurons (ORN) elongate their axons to penetrate the brain basement membrane, contact and form synapses with projection neurons of the olfactory bulb primordium. Axonal elongation is accompanied by migration of the GnRH+ neurons, followed by their ingression in the septo-hypothalamic area of the forebrain. This process is specifically impaired in the Kallmann’s syndrome (KS), a disorder characterized by anosmia and central hypogonadism. A set of transcription factors are master regulators of olfactory connectivity and GnRH neuron migration. We explored the transcriptional network underlying this process, by profiling the OE and adjacent mesenchyme at distinct embryonic ages. We also profiled the OE from embryos null for Dlx5, a homeogene essential for olfactory development, that causes a KS-like phenotype when deleted. We also applied analysis of conserved co-expression to integrate the obtained data with information on KS disease genes. The prevalent categories of genes differentially expressed during development are neuronal differentiation, extracellular remodelling and cell adhesion. From the analysis of Dlx5 mutant tissues we identify about 120 genes with a prevalence of intermediate filaments, cell signalling, epithelial and neuronal differentiation. Filtering for true OE expression and for the presence of Dlx5 binding sites, yielded twenty genes, of the following categories: 1) transmembrane adhesion/receptor molecules, 2) axon-glia interaction molecules, 3) synaptic proteins, 4) scaffold/adapter for signalling molecules. To functionally analyze these genes in vivo, we used three zebrafish fluorescent reporter zebrafish strains, in which we monitored early phases of olfactory/GnRH development upon gene downmodulation. The depletion of three (of five) Dlx5 targets affected axonal extension and targeting, while two (of two) altered GnRH neuron position and neurite organization.

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Illuminating the terminal nerve: Uncovering the link between GnRH-1 neuron and olfactory development

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